ISOC1 Modulates Inflammatory Responses in Macrophages through the AKT1/PEX11B/Peroxisome Pathway.

Inflammation underlies a variety of physiological and pathological processes and plays an essential role in shaping the ensuing adaptive immune responses and in the control of pathogens. However, its physiological functions are not completely clear. Using a LPS-treated RAW264.7 macrophage inflammation model, we found that the production of inflammatory cytokines in ISOC1-deficient cells was significantly higher than that in the control group. It was further proved that ISOC1 deficiency could activate AKT1, and the overactivation of AKT1 could reduce the stability of PEX11B through protein modification, thereby reducing the peroxisome biogenesis and thus affecting inflammation. In this study, we reported for the first time the role of ISOC1 in innate immunity and elucidated the mechanism by which ISOC1 regulates inflammation through AKT1/PEX11B/peroxisome. Our results defined a new role of ISOC1 in the regulatory mechanism underlying the LPS-induced inflammatory response.

Vitamin C-induced competitive binding of HIF-1α and p53 to ubiquitin E3 ligase CBL contributes to anti-breast cancer progression through p53 deacetylation.

Vitamin C (VC), in regard to its effectiveness against tumors, has had a controversial history in cancer treatment. However, the anticancer mechanisms of VC are not fully understood. Here, we reported that VC exerted an anticancer effect on cancer cell and xenograft models via inhibiting HIF-1α-dependent cell proliferation and promoting p53-dependent cell apoptosis. To be specific, VC modulated the competitive binding of HIF-1α and p53 to their common E3 ubiquitin ligase CBL, thereby inhibiting tumorigenesis. Moreover, VC treatment activated SIRT1, resulting in p53 deacetylation and CBL-p53 complex dissociation, which in turn facilitated CBL recruitment of HIF-1α for ubiquitination in a proteasome-dependent manner. Altogether, our results provided a mechanistic rationale for exploring the therapeutic use of VC in cancer therapy.

Tgm2 alleviates LPS-induced apoptosis by inhibiting JNK/BCL-2 signaling pathway through interacting with Aga in macrophages.

Sepsis is an unusual systemic infection caused by bacteria, which is a life-threatening organ dysfunction. The innate immune system plays an important role in this process; however, the specific mechanisms remain unclear. Using the LPS + treated mouse model, we found that the survival rate of Tgm2-/- mice was lower than that of the control group, while the inflammation was much higher. We further showed that Tgm2 suppressed apoptosis by inhibiting the JNK/BCL-2 signaling pathway. More importantly, Tgm2 interacted with Aga and regulated mitochondria-mediated apoptosis induced by LPS. Our findings elucidated a protective mechanism of Tgm2 during LPS stimulation and may provide a new reference target for the development of novel anti-infective drugs from the perspective of host immunity.

MiR-342 controls Mycobacterium tuberculosis susceptibility by modulating inflammation and cell death.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that places a heavy strain on public health. Host susceptibility to Mtb is modulated by macrophages, which regulate the balance between cell apoptosis and necrosis. However, the role of molecular switches that modulate apoptosis and necrosis during Mtb infection remains unclear. Here, we show that Mtb-susceptible mice and TB patients have relatively low miR-342-3p expression, while mice with miR-342-3p overexpression are more resistant to Mtb. We demonstrate that the miR-342-3p/SOCS6 axis regulates anti-Mtb immunity by increasing the production of inflammatory cytokines and chemokines. Most importantly, the miR-342-3p/SOCS6 axis participates in the switching between Mtb-induced apoptosis and necrosis through A20-mediated K48-linked ubiquitination and RIPK3 degradation. Our findings reveal several strategies by which the host innate immune system controls intracellular Mtb growth via the miRNA-mRNA network and pave the way for host-directed therapies targeting these pathways.

ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway.

Recently, COVID-19 caused by the novel coronavirus SARS-CoV-2 has brought great challenges to the world. More and more studies have shown that patients with severe COVID-19 may suffer from cytokine storm syndrome; however, there are few studies on its pathogenesis. Here we demonstrated that SARS-CoV-2 coding protein open reading frame 8 (ORF8) acted as a contributing factor to cytokine storm during COVID-19 infection. ORF8 could activate IL-17 signaling pathway and promote the expression of pro-inflammatory factors. Moreover, we demonstrated that treatment of IL17RA antibody protected mice from ORF8-induced inflammation. Our findings are helpful to understand the pathogenesis of cytokine storm caused by SARS-CoV-2 and provide a potential target for the development of COVID-19 therapeutic drugs.

PTPN14 aggravates inflammation through promoting proteasomal degradation of SOCS7 in acute liver failure.

Acute liver failure (ALF) is a rare but life-threatening systemic disorder. The innate immune regulation has an important role in this process; however, the specific mechanisms are not completely clear. Using the LPS + D-GalN-induced ALF mouse model, we found that the survival rate of PTPN14-deficient mice was higher than that of the control group, while the release of inflammatory factors was significantly lower. We further showed that PTPN14 interacted with SOCS7, and promoted the degradation of SOCS7 through ubiquitination at K11 and K48, thereby reducing the protein level of SOCS7 and weakening the inhibitory effects on inflammatory factors. More importantly, SOCS7 blocked the NF-κB signaling pathway by preventing the activity of the IKK complex, and then reduced the expression of downstream inflammatory factors. In this study, we firstly reported the inhibitory effect of SOCS7 on the NF-κB pathway in the ALF mouse model and elucidated the mechanism of PTPN14-SOCS7-NF-κB axis in the regulation of inflammation. These results provide new insights into the clinical treatment of ALF.

MicroRNA-325-3p Facilitates Immune Escape of Mycobacterium tuberculosis through Targeting LNX1 via NEK6 Accumulation to Promote Anti-Apoptotic STAT3 Signaling.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that poses threats to the public. M. tuberculosis survives in macrophages by escaping from immune surveillance and clearance, which exacerbates the bacterial proliferation. However, the molecular mechanisms of this immune escape have not yet been fully understood. Using multiple cell and mouse models, we found that microRNA-325-3p (miR-325-3p) is upregulated after M. tuberculosis infection and Mir325-deficient mice show resistance to M. tuberculosis We demonstrated that miR-325-3p directly targets LNX1, an E3 ubiquitin ligase of NEK6, and that this hampers the proteasomal degradation of NEK6 in macrophages. The abnormal accumulation of NEK6 leads to the activation of STAT3 signaling, thus inhibiting the process of apoptosis and promoting the intracellular survival of M. tuberculosis Our findings not only reveal a new immune escape pathway of M. tuberculosis but also may provide new insights into the development of therapeutic approaches for drug-resistant TB.IMPORTANCE Intracellular survival of Mycobacterium tuberculosis results in bacterial proliferation and the spread of infection in lungs, consequently deteriorating the conditions of tuberculosis (TB) patients. This research discovers a new immune escape pathway of M. tuberculosis by modulating host miR-325-3p expression, thus leading to the intracellular survival of M. tuberculosis These findings make a contribution to the understanding of the immune escape of M. tuberculosis, and they provide a theoretical basis for the development of therapeutic approaches for drug-resistant TB.