Mendelian randomization unraveled: gender-specific insights into obesity-related phenotypes and colorectal cancer susceptibility.

Objective: Evidence has been increasingly pointing towards a potential link between phenotypes related to obesity and the incidence of colorectal cancer. However, confirming this as a direct causal connection remains elusive. This investigation aims to elucidate the causative links between obesity-associated phenotypes and the incidence of colorectal cancer. Methods: Employing the Two Sample Mendelian Randomization (TwoSampleMR) R package, analyses were conducted using Mendelian randomization (MR) to discern potential causative links between obesity categories sourced from both the Institute for Education and University (IEU) Open GWAS Project and Zenodo, and colorectal tumors (data obtained from IEU Open GWAS and FinnGen). For primary evaluations, the study utilized the Wald ratio and the Inverse Variance Weighting (IVW) methods, while the MR-Egger approach was integrated for sensitivity assessment. Bidirectional Mendelian Randomization (Bidirectional MR), as well as Linkage Disequilibrium (LD) Score Regression with well-imputed HapMap3 single nucleotide polymorphisms (SNPs), were additionally executed. Sensitivity assessments entailed IVW, MR-Egger methodologies to assess heterogeneity and pleiotropy, along with a leave-one-out strategy. Instrumental variables were chosen judiciously based on predetermined P-value thresholds and F-statistics. Results: Results from MR evaluations did not identify a clear causative link between BMI and colorectal malignancy. Conversely, both measures of obesity, the Waist-Hip Ratio (WHR) and its adjusted form for BMI (WHRadjBMI), displayed a connection to increased risk of colorectal cancer, especially prominent among female subjects. Reverse MR analyses dismissed potential reverse causality between colorectal malignancies and obesity. A significant genetic interplay was observed between WHR, WHRadjBMI, and colorectal cancer instances. Ensuing MR probes spotlighted inflammatory bowel ailment as a protective factor, while salad intake was indicated as a potential risk concerning colorectal malignancies. Sensitivity reviews, which included tests for both pleiotropy and heterogeneity, validated the robustness of the MR findings. Conclusion: Findings from this research indicate that specific obesity-related parameters, notably WHR and WHRadjBMI, carry a causal relationship with an elevated colorectal cancer risk. The impact is distinctly more evident among females. Such insights might be pivotal for public health deliberations, hinting that individuals boasting a high WHR might necessitate intensified colorectal cancer screenings.

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives.

Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically for cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies and peptides, along with innovative approaches like the use of kinase degraders and protein kinase interaction inhibitors, which have recently demonstrated clinical progress and potential in overcoming resistance. Nevertheless, kinase-targeted strategies encounter significant hurdles, including drug resistance, which greatly impacts the clinical benefits for cancer patients, as well as concerning toxicity when combined with immunotherapy, which restricts the full utilization of current treatment modalities. Despite these challenges, the development of kinase inhibitors remains highly promising. The extensively studied tyrosine kinase family has 70% of its targets in various stages of development, while 30% of the kinase family remains inadequately explored. Computational technologies play a vital role in accelerating the development of novel kinase inhibitors and repurposing existing drugs. Recent FDA-approved SMKIs underscore the importance of blood-brain barrier permeability for long-term patient benefits. This review provides a comprehensive summary of recent FDA-approved SMKIs based on their mechanisms of action and targets. We summarize the latest developments in potential new targets and explore emerging kinase inhibition strategies from a clinical perspective. Lastly, we outline current obstacles and future prospects in kinase inhibition.

Whole-brain spatial organization of hippocampal single-neuron projectomes.

Mapping single-neuron projections is essential for understanding brain-wide connectivity and diverse functions of the hippocampus (HIP). Here, we reconstructed 10,100 single-neuron projectomes of mouse HIP and classified 43 projectome subtypes with distinct projection patterns. The number of projection targets and axon-tip distribution depended on the soma location along HIP longitudinal and transverse axes. Many projectome subtypes were enriched in specific HIP subdomains defined by spatial transcriptomic profiles. Furthermore, we delineated comprehensive wiring diagrams for HIP neurons projecting exclusively within the HIP formation (HPF) and for those projecting to both intra- and extra-HPF targets. Bihemispheric projecting neurons generally projected to one pair of homologous targets with ipsilateral preference. These organization principles of single-neuron projectomes provide a structural basis for understanding the function of HIP neurons.

Repurposing drugs for solid tumor treatment: focus on immune checkpoint inhibitors.

Cancer remains a significant global health challenge with limited treatment options beyond systemic therapies, such as chemotherapy, radiotherapy, and molecular targeted therapy. Immunotherapy has emerged as a promising therapeutic modality but the efficacy has plateaued, which therefore provides limited benefits to patients with cancer. Identification of more effective approaches to improve patient outcomes and extend survival are urgently needed. Drug repurposing has emerged as an attractive strategy for drug development and has recently garnered considerable interest. This review comprehensively analyses the efficacy of various repurposed drugs, such as transforming growth factor-beta (TGF-ß) inhibitors, metformin, receptor activator of nuclear factor-κB ligand (RANKL) inhibitors, granulocyte macrophage colony-stimulating factor (GM-CSF), thymosin α1 (Tα1), aspirin, and bisphosphonate, in tumorigenesis with a specific focus on their impact on tumor immunology and immunotherapy. Additionally, we present a concise overview of the current preclinical and clinical studies investigating the potential therapeutic synergies achieved by combining these agents with immune checkpoint inhibitors.

Clinical, hormonal, and biochemical characteristics of 70 chinese children with moderate to severe type 1 diabetic ketoacidosis.

BACKGROUND: Diabetic ketoacidosis (DKA) is one of the most severe acute complications of type 1 diabetes mellitus (T1DM). Patients with DKA of different severities may have different clinical manifestations, serum biochemical levels and hormone changes. METHODS: We retrospectively evaluated the clinical manifestations, serum hormone levels, and biochemical levels of 70 Chinese patients with moderate to severe type 1 DKA in the acute and recovery phases admitted to Shanghai Children's Hospital from 2015 to 2020. RESULTS: The time required for acidosis correction in 37 patients with severe DKA was 5.9 h longer than that in 33 patients with moderate DKA (P < 0.001). In addition, serum levels of serum ionized calcium (P = 0.003), free triiodothyronine (FT3) (P = 0.029), white blood cells (WBCs) (P = 0.044), and triglycerides (TGs) (P = 0.002) were significantly different between patients with moderate and severe DKA. Serum levels of ionized calcium decreased significantly after recovery from severe DKA. Within 1 week, thyroid hormone and blood lipid levels recovered to normal ranges without intervention. CONCLUSION: Patients with severe DKA had higher acidosis correction times, higher WBC counts, TGs and ionized calcium levels, and lower FT3 levels than patients with moderate DKA. No additional intervention was required for thyroid hormone, and blood lipid and serum ionized calcium levels recovered to the normal range.

Clinical, Hormonal, and Genetic Characteristics of 5α-Reductase Type 2 Deficiency in 103 Chinese Patients.

OBJECTIVE: 5α-Reductase type 2 (5α-RD2) deficiency causes variable degrees of undervirilization in patients. The correlation between its genotype and phenotype is unclear. METHODS: We retrospectively evaluated 103 patients with 46,XY disorders of sex development who were diagnosed with 5α-RD2 deficiency. RESULTS: The prevalence of female sex assignment (P = .008) and the incidences of cryptorchidism (P = .0003) and bifid scrotum (P = .0002) in the non-p.R227Q variant group were higher, but there were no significant differences in the incidences of hypospadias and isolated microphallus. The external masculinization score in the non-p.R227Q variant group was lower than that in the homozygous p.R227Q variant (P = .019) and compound heterozygous p.R227Q variant groups (P = .013). The level of anti-Mullerian hormone in the non-p.R227Q variant group was lower than that in the homozygous p.R227Q variant (P < .001) and compound heterozygous p.R227Q variant groups (P = .006). The testosterone-to-dihydrotestosterone ratio of the homozygous p.R227Q variant group was higher than that of the non-p.R227Q variant (P = .018) and compound heterozygous p.R227Q variant groups (P = .029). Twenty-three reportedly pathogenic variants and 11 novel steroid 5α-reductase 2 (SRD5A2) variants were identified. CONCLUSION: Compared with patients without p.R227Q, patients with p.R227Q exhibited higher external masculinization scores and anti-Mullerian hormone expression, a lower prevalence of female sex assignment, and lower incidences of cryptorchidism and bifid scrotum. We identified 23 reportedly pathogenic SRD5A2 variants and 11 novel SRD5A2 variants that led to 5α-RD2 deficiency. We established a genotype-phenotype correlation, and patients with p.R227Q showed a relatively mild phenotype.

Single-neuron projectome of mouse prefrontal cortex.

Prefrontal cortex (PFC) is the cognitive center that integrates and regulates global brain activity. However, the whole-brain organization of PFC axon projections remains poorly understood. Using single-neuron reconstruction of 6,357 mouse PFC projection neurons, we identified 64 projectome-defined subtypes. Each of four previously known major cortico-cortical subnetworks was targeted by a distinct group of PFC subtypes defined by their first-order axon collaterals. Further analysis unraveled topographic rules of soma distribution within PFC, first-order collateral branch point-dependent target selection and terminal arbor distribution-dependent target subdivision. Furthermore, we obtained a high-precision hierarchical map within PFC and three distinct functionally related PFC modules, each enriched with internal recurrent connectivity. Finally, we showed that each transcriptome subtype corresponds to multiple projectome subtypes found in different PFC subregions. Thus, whole-brain single-neuron projectome analysis reveals organization principles of axon projections within and outside PFC and provides the essential basis for elucidating neuronal connectivity underlying diverse PFC functions.

Clinical, hormonal, and genetic characteristics of 25 Chinese patients with idiopathic hypogonadotropic hypogonadism.

BACKGROUND: Idiopathic hypogonadotropic hypogonadism (IHH) is a type of congenital disease caused by a variety of gene variants leading to dysfunction in the secretion of hypothalamic gonadotropin-releasing hormones (GnRHs). Clinically, IHH can be divided into Kallmann syndrome (KS) with dysosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH) according to the presence or absence of an olfactory disorder. METHODS: We retrospectively evaluated 25 IHH patients (8 KS and 17 nIHH) who were diagnosed at the Department of Endocrinology of Shanghai Children's Hospital from 2015 to 2021. We analysed the patients' clinical data, including their hormone levels and gene sequences. RESULTS: All male patients exhibited small phalli, and 35% of them exhibited cryptorchidism. A significant difference was observed in the levels of dihydrotestosterone (DHT) after human chorionic gonadotropin (HCG) stimulation (P = 0.028) between the KS group and the nIHH group. Missense variants were the major cause of IHH, and the main pathogenic genes were FGFR1, PROKR2/PROK2, and KAl1. Nine reported and 13 novel variants of six genes were identified. De novo variants were detected in 16 IHH patients; eight patients inherited the variants from their mothers, while only three patients inherited variants from their fathers. One patient had both KAl1 and PROKR2 gene variants, and another patient had two different PROKR2 gene variants. These two patients both had the hot spot variant c.533G > C (p. Trp178Ser) of the PROKR2 gene. CONCLUSION: IHH should be highly suspected in patients with a small phallus and cryptorchidism. Compared with nIHH patients, KS patients exhibited a higher level of DHT after HCG stimulation. Missense variants were the major cause of IHH, and most of the inherited variants were from their mothers who exhibited no obvious clinical symptoms. We identified 9 reported variants and 13 novel variants that led to IHH. A small proportion of patients were at risk of inheriting either the oligogenic variant or the compound heterozygous variant. The hot spot variant c.533G > C (p. Trp178Ser) of PROKR2 might be involved in oligogenic inheritance and compound heterozygous inheritance. These findings provide deeper insight into the diagnosis and classification of IHH and will contribute to its clinical assessment.

Glycogen accumulation and phase separation drives liver tumor initiation.

Glucose consumption is generally increased in tumor cells to support tumor growth. Interestingly, we report that glycogen accumulation is a key initiating oncogenic event during liver malignant transformation. We found that glucose-6-phosphatase (G6PC) catalyzing the last step of glycogenolysis is frequently downregulated to augment glucose storage in pre-malignant cells. Accumulated glycogen undergoes liquid-liquid phase separation, which results in the assembly of the Laforin-Mst1/2 complex and consequently sequesters Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme-liver glycogen phosphorylase (PYGL) deficiency in both human and mice results in glycogen storage disease along with liver enlargement and tumorigenesis in a Yap-dependent manner. Consistently, elimination of glycogen accumulation abrogates liver growth and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that cancer-initiating cells adapt a glycogen storing mode, which blocks Hippo signaling through glycogen phase separation to augment tumor incidence.

Clinical, hormonal and genetic characteristics of androgen insensitivity syndrome in 39 Chinese patients.

BACKGROUND: Abnormal androgen receptor (AR) genes can cause androgen insensitivity syndrome (AIS), and AIS can be classified into complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS) and mild AIS. We investigated the characteristics of clinical manifestations, serum sex hormone levels and AR gene mutations of 39 AIS patients, which provided deeper insight into this disease. METHODS: We prospectively evaluated 39 patients with 46, XY disorders of sex development (46, XY DSD) who were diagnosed with AIS at the Department of Endocrinology of Shanghai Children's Hospital from 2014 to 2019. We analysed clinical data from the patients including hormone levels and AR gene sequences. Furthermore, we screened the AR gene sequences of the 39 AIS patients to identify probable mutations. RESULTS: The 39 AIS patients came from 37 different families; 19 of the patients presented CAIS, and 20 of them presented PAIS. The CAIS patients exhibited a higher cryptorchidism rate than the PAIS (100 and 55%, P = 0.001). There were no significant difference between the CAIS and PAIS groups regarding the levels of inhibin B (INHB), sex hormone-binding globulin (SHBG), basal luteinizing hormone (LH), testosterone (T), or basal dihydrotestosterone (DHT), the T:DHT ratio, DHT levels after human chorionic gonadotropin (HCG) stimulation or T levels after HCG stimulation. However, the hormone levels of AMH (P = 0.010), peak LH (P = 0.033), basal FSH (P = 0.009) and peak FSH (P = 0.033) showed significant differences between the CAIS group and the PAIS group. Twenty-one reported pathogenic and 9 novel AR mutations were identified. Spontaneous AR mutations were found in 5 AIS patients, and 21 patients inherited mutations from their mothers, who carried heterozygous mutations. CONCLUSIONS: Forty-six XY DSD patients with cryptorchidism and female phenotypes were highly suspected of having AIS. We demonstrated that CAIS patients could not be distinguished by their hormone levels alone. Compared with PAIS patients, CAIS patients exhibited higher basal FSH, peak FSH, and peak LH hormone levels but lower AMH expression. We identified 21 reported pathogenic AR mutations and 9 novel AR mutations that led to different types of AIS. Missense mutations were the major cause of AIS and mostly occurred in exon 7 of the AR gene. These findings provided deeper insight into the diagnosis and classification of AIS and will even contributed to its clinical assessment.

Diagnostic value of hepatic artery perfusion fraction combined with TGF-ß in patients with hepatocellular carcinoma.

Diagnostic value of hepatic artery perfusion fraction (HAF) combined with transforming growth factor-ß (TGF-ß) in the diagnosis of primary liver carcinoma (PLC) was evaluated. The clinical data of 128 PLC patients undergoing radical hepatectomy in Affiliated Hospital of Jining Medical University were regarded as the study group. Seventy-four healthy volunteers examined in Affiliated Hospital of Jining Medical University were collected as the control group. Double-antibody sandwich enzyme-linked immunosorbent assay was used to detect the expression level of serum TGF-ß. The upper abdomen of the subjects was scanned by a 64-slice spiral CT, and the perfusion parameters were analyzed and calculated. According to the HAF and the expression level of TGF-ß in the two groups, single and combined detection of TGF-ß and HAF parameters were detected, respectively, by ROC curve. The expression of TGF-ß in serum of the study group was higher than that of the control group (P<0.05). The expression level of serum TGF-ß was closely related to total bilirubin, ascites, TNM stage, prothrombin time and tumor diameter. Blood flow (BF), blood volume (BV), permeability surface (PS), HAF and other perfusion parameters in the study group were higher than those in the control group (P<0.05). The specificity and sensitivity of TGF-ß expression level in diagnosing PLC were 73 and 93%, respectively; the specificity and sensitivity of HAF parameter in diagnosing PLC were 73 and 100%, respectively; the specificity and sensitivity of HAF parameter combined with TGF-ß expression level were 84 and 100%, respectively. TGF-ß is highly expressed in serum of PLC patients; HAF parameter combined with TGF-ß expression level can improve the specificity and has an important value in the diagnosis of PLC, which is worthy of clinical promotion.

FGF15 Activates Hippo Signaling to Suppress Bile Acid Metabolism and Liver Tumorigenesis.

The external factors that modulate Hippo signaling remain elusive. Here, we report that FGF15 activates Hippo signaling to suppress bile acid metabolism, liver overgrowth, and tumorigenesis. FGF15 is induced by FXR in ileal enterocytes in response to increased amounts of intestinal bile. We found that circulating enterohepatic FGF15 stimulates hepatic receptor FGFR4 to recruit and phosphorylate NF2, which relieves the inhibitory effect of Raf on the Hippo kinases Mst1/2, thereby switching FGFR4's role from pro-oncogenic to anti-tumor signaling. The activated Mst1/2 subsequently phosphorylates and stabilizes SHP to downregulate the key bile acid-synthesis enzyme Cyp7a1 expression, thereby limiting bile acid synthesis. In contrast, Mst1/2 deficiency impairs bile acid metabolism and remarkably increases Cyp7a1 expression and bile acid production. Importantly, pharmacological depletion of intestinal bile abrogates Mst1/2-mutant-driven liver overgrowth and oncogenesis. Therefore, FGF15-Hippo signaling along the gut-liver axis acts as a sensor of bile acid availability to restrain liver size and tumorigenesis.

The Hippo Signaling Pathway in Regenerative Medicine.

The major role of Hippo signaling is to inhibit their downstream effectors YAP/TAZ for organ size control during development and regeneration (Nat Rev Drug Discov 13(1):63-79, 2014; Dev Cell 19(4):491-505, 2010; Cell 163(4):811-828, 2015). We and others have demonstrated that the genetic disruption of kinases Mst1 and Mst2 (Mst1/2), the core components of Hippo signaling, results in YAP activation and sustained liver growth, thereby leading to an eight- to tenfold increase in liver size within 3 months and occurrence of liver cancer within 5 months (Curr Biol 17(23):2054-2060, 2007; Cancer Cell 16(5):425-438, 2009; Cell 130(6):1120-1133, 2007; Cancer Cell 31(5):669-684 e667, 2017; Nat Commun 6:6239, 2015; Cell Rep 3(5):1663-1677, 2013). XMU-MP-1, an Mst1/2 inhibitor, is able to augment mouse liver and intestinal repair and regeneration in both acute and chronic injury mouse models (Sci Transl Med 8:352ra108, 2016).In addition, YAP-deficient mice show an impaired intestinal regenerative response after DSS treatment or gamma irradiation (Proc Natl Acad Sci U S A 108(49):E1312-1320, 2011; Nature 493(7430):106-110, 2013; Genes Dev 24(21):2383-2388, 2010; J Vis Exp (111), 2010). IBS008738, a TAZ activator, facilitates muscle repair after cardiotoxin-induced muscle injury (Mol Cell Biol. 2014;34(9):1607-21). Deletion of Salvador (Sav) in mouse hearts enhances cardiomyocyte regeneration with reduced fibrosis and recovery of pumping function after myocardial infarction (MI) or resection of mouse cardiac apex (Development 140(23):4683-4690, 2013; Sci Signal 8(375):ra41, 2015; Nature 550(7675):260-264, 2017). This chapter provides a detailed description of procedures and important considerations when performing the protocols for the respective assays used to determine the effects of Hippo signaling on tissue repair and regeneration.

Increased glycoprotein acetylation is associated with high cardiac event rates: Analysis using coronary computed tomography angiography.

OBJECTIVE: Glycoprotein acetylation (GlycA), an emerging inflammatory biomarker, has been used as an indicator of cardiovascular disease. Our research aimed to evaluate the correlation between GlycA and coronary artery disease (CAD) using coronary computed tomography angiography (CCTA). METHODS: In the present study, a total of 342 patients were enrolled, and each of them underwent CCTA. The correlation between GlycA and major adverse cardiac events (MACE) was detected via Cox's proportional hazards models. Based on differences in the GlycA level, patients were categorized into three groups (T1, T2, and T3). RESULTS: Compared with the group with the lowest GlycA level (T1), the group with the highest GlycA level (T3) exhibited stronger atherosclerotic pressure involving the extent of atherosclerotic plaque and risk of obstructive CAD. In addition, the patients in the T3 group had a greater chance of experiencing MACE and higher all-cause mortality than those in the T1 group. Among patients without CAD who underwent CCTA, those with high GlycA levels experienced elevated atherosclerotic stress and heightened risk of MACE compared with those with low GlycA levels. CONCLUSION: These results suggest that serum GlycA is significantly associated with the long-term clinical results of patients with no known CAD undergoing CCTA. The risks of death and experiencing MACE increase among patients with high GlycA levels.

Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2.

Polyploidy can lead to aneuploidy and tumorigenesis. Here, we report that the Hippo pathway effector Yap promotes the diploid-polyploid conversion and polyploid cell growth through the Akt-Skp2 axis. Yap strongly induces the acetyltransferase p300-mediated acetylation of the E3 ligase Skp2 via Akt signaling. Acetylated Skp2 is exclusively localized to the cytosol, which causes hyper-accumulation of the cyclin-dependent kinase inhibitor p27, leading to mitotic arrest and subsequently cell polyploidy. In addition, the pro-apoptotic factors FoxO1/3 are overly degraded by acetylated Skp2, resulting in polyploid cell division, genomic instability, and oncogenesis. Importantly, the depletion or inactivation of Akt or Skp2 abrogated Hippo signal deficiency-induced liver tumorigenesis, indicating their epistatic interaction. Thus, we conclude that Hippo-Yap signaling suppresses cell polyploidy and oncogenesis through Skp2.

Genetic variants in the plasminogen activator inhibitor-1 gene are associated with an increased risk of radiation pneumonitis in lung cancer patients.

Plasminogen activator inhibitor-1 (PAI-1) plays a crucial role in the process of lung injury, although its association with radiation pneumonitis (RP) is unclear. We hypothesized that genetic variants in PAI-1 may influence the risk of RP. In this study, 169 lung cancer patients were genotyped for six single-nucleotide polymorphisms in PAI-1 using the Sequenom MassARRAY system. The risk of RP was evaluated by Cox proportional hazards analyses. The cumulative RP probabilities by genotype were assessed using Kaplan-Meier analyses. Univariate and multivariate analyses revealed that PAI-1:rs7242 GT/GG was correlated with an increased occurrence of grade ≥3 RP (crude hazard ratio = 3.331; 95% confidence interval, 1.168-9.497; P = 0.024). Our results indicated that PAI-1:rs7242 in the 3'-untranslated region of PAI-1 can be a predictor of grade ≥3 RP before radiotherapy.

MMP-1 promoter polymorphism is associated with risk of radiation-induced lung injury in lung cancer patients treated with radiotherapy.

Matrix metalloproteinase-1 (MMP-1) has been implicated in several inflammatory and fibrotic diseases. We hypothesized that genetic variations in the MMP1 promoter region are associated with risk of radiation-induced lung injury (RILI). A cohort of 251 lung cancer patients was genotyped for five single nucleotide polymorphisms in the MMP1 promoter region. We found that rs1144393 AG/GG was strongly correlated with an increased occurrence of grade ≥ 2 RILI (p = 0.002). Additionally, patients with the rs1144393 AG/GG genotypes exhibited higher MMP-1 expression than patients with the AA genotype in lung tissues (n = 28, p = 0.022) and plasma samples (n = 40, p = 0.018). Our results indicated that rs1144393 in the MMP1 promoter region can be a predictor of grade ≥ 2 RILI in lung cancer patients treated with thoracic radiation.

Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity.

Mitochondria need to be juxtaposed to phagosomes for the synergistic production of ample reactive oxygen species (ROS) in phagocytes to kill pathogens. However, how phagosomes transmit signals to recruit mitochondria has remained unclear. Here we found that the kinases Mst1 and Mst2 functioned to control ROS production by regulating mitochondrial trafficking and mitochondrion-phagosome juxtaposition. Mst1 and Mst2 activated the GTPase Rac to promote Toll-like receptor (TLR)-triggered assembly of the TRAF6-ECSIT complex that is required for the recruitment of mitochondria to phagosomes. Inactive forms of Rac, including the human Rac2(D57N) mutant, disrupted the TRAF6-ECSIT complex by sequestering TRAF6 and substantially diminished ROS production and enhanced susceptibility to bacterial infection. Our findings demonstrate that the TLR-Mst1-Mst2-Rac signaling axis is critical for effective phagosome-mitochondrion function and bactericidal activity.

Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis.

The role of the unfolded protein response (UPR) in tissue homeostasis remains largely unknown. Here we find that loss of Mst1/2, the mammalian Hippo orthologues, or their regulator WW45, leads to a remarkably enlarged endoplasmic reticulum (ER) size-associated UPR. Intriguingly, attenuation of the UPR by tauroursodeoxycholic acid (TUDCA) diminishes Mst1/2 mutant-driven liver overgrowth and tumorigenesis by promoting nuclear exit and degradation of Hippo downstream effector Yap. Yap is required for UPR activity and ER expansion to alleviate ER stress. During the adaptive stage of the UPR, PERK kinase-eIF2α axis activates Yap, while prolonged ER stress-induced Hippo signalling triggers assembly of the GADD34/PP1 complex in a negative feedback loop to inhibit Yap and promote apoptosis. Significantly, the deregulation of UPR signals associated with Yap activation is found in a substantial fraction of human hepatocellular carcinoma (HCC). Thus, we conclude Yap integrates Hippo and UPR signalling to control liver size and tumorigenesis.