Drice restrains Diap2-mediated inflammatory signalling and intestinal inflammation.

The Drosophila IAP protein, Diap2, is a key mediator of NF-κB signalling and innate immune responses. Diap2 is required for both local immune activation, taking place in the epithelial cells of the gut and trachea, and for mounting systemic immune responses in the cells of the fat body. We have found that transgenic expression of Diap2 leads to a spontaneous induction of NF-κB target genes, inducing chronic inflammation in the Drosophila midgut, but not in the fat body. Drice is a Drosophila effector caspase known to interact and form a stable complex with Diap2. We have found that this complex formation induces its subsequent degradation, thereby regulating the amount of Diap2 driving NF-κB signalling in the intestine. Concordantly, loss of Drice activity leads to accumulation of Diap2 and to chronic intestinal inflammation. Interestingly, Drice does not interfere with pathogen-induced signalling, suggesting that it protects from immune responses induced by resident microbes. Accordingly, no inflammation was detected in transgenic Diap2 flies and Drice-mutant flies reared in axenic conditions. Hence, we show that Drice, by restraining Diap2, halts unwanted inflammatory signalling in the intestine.

Telemedicine During the COVID-19 Pandemic: A Paradigm Shift in Non-Communicable Disease Management? - A Cross-Sectional Survey from a Quaternary-Care Center in South India.

PURPOSE: This study aims to gauge the perception and adoption rates of telemedicine amongst patients with non-communicable diseases (NCD) as opposed to in-person consultations in a quaternary care center in South India. PATIENTS AND METHODS: A web-hosted 21-item cross-sectional survey was distributed to 220 randomly selected patients with a routine appointment in one of the seven departments caring for NCDs in the study center. Descriptive analysis and inferential analyses were done. Paired samples T-test and Pearson's Chi-square test were used study associations. RESULTS: In-person consultations decreased by 1.9±4.47 visits per year, in 2020 vs 2019. Most participants reported "fear of COVID-19" as the primary reason for this decline. Participants also reported that their consultation times had significantly decreased (OR=6.43, 95% CI=1.7-24.08, p=0.006). The decreased consultations time, difficulty in obtaining in-person appointments, along with the reduced physical examination during consultations have made participants more open to the idea of teleconsultations (OR=3.88, 95% CI=1.21-12.47, p=0.022). Eighty-five (38.63%) participants had already adopted telemedicine for their routine consultations during the pandemic. Whilst participants felt that telemedicine was an adequate surrogate for in-person consultations, a significant difficulty in obtaining medications was noted (OR=6, 95% CI=1.34-26.81, p=0.019). CONCLUSION: In-person consultations were decreased primarily due to the perception of significant risk of COVID-19 exposure in the present scenario. Telemedicine adoption in the private sector may be sustainable throughout the pandemic and beyond, if patients are offered to continue their routine consultations with their regular doctors and ensured medicine availability. Integration of telemedicine by the public and private health sector of India into routine NCD care delivery is the need of the hour, but further studies are required to estimate the effectiveness of the systems.

UBR5 Is Coamplified with MYC in Breast Tumors and Encodes an Ubiquitin Ligase That Limits MYC-Dependent Apoptosis.

For maximal oncogenic activity, cellular MYC protein levels need to be tightly controlled so that they do not induce apoptosis. Here, we show how ubiquitin ligase UBR5 functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 ubiquitinates MYC and its effects on MYC protein stability are independent of FBXW7. Silencing of endogenous UBR5 induced MYC protein expression and regulated MYC target genes. Consistent with the tumor suppressor function of UBR5 (HYD) in Drosophila, HYD suppressed dMYC-dependent overgrowth of wing imaginal discs. In contrast, in cancer cells, UBR5 suppressed MYC-dependent priming to therapy-induced apoptosis. Of direct cancer relevance, MYC and UBR5 genes were coamplified in MYC-driven human cancers. Functionally, UBR5 suppressed MYC-mediated apoptosis in p53-mutant breast cancer cells with UBR5/MYC coamplification. Furthermore, single-cell immunofluorescence analysis demonstrated reciprocal expression of UBR5 and MYC in human basal-type breast cancer tissues. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC activity. In MYC-amplified, and p53-mutant breast cancer cells, UBR5 has an important role in suppressing MYC-mediated apoptosis priming and in protection from drug-induced apoptosis. SIGNIFICANCE: These findings identify UBR5 as a novel MYC regulator, the inactivation of which could be very important for understanding of MYC dysregulation on cancer cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1414/F1.large.jpg.

M1-linked ubiquitination by LUBEL is required for inflammatory responses to oral infection in Drosophila.

Post-translational modifications such as ubiquitination play a key role in regulation of inflammatory nuclear factor-κB (NF-κB) signalling. The Drosophila IκB kinase γ (IKKγ) Kenny is a central regulator of the Drosophila Imd pathway responsible for activation of the NF-κB Relish. We found the Drosophila E3 ligase and HOIL-1L interacting protein (HOIP) orthologue linear ubiquitin E3 ligase (LUBEL) to catalyse formation of M1-linked linear ubiquitin (M1-Ub) chains in flies in a signal-dependent manner upon bacterial infection. Upon activation of the Imd pathway, LUBEL modifies Kenny with M1-Ub chains. Interestingly, the LUBEL-mediated M1-Ub chains seem to be targeted both directly to Kenny and to K63-linked ubiquitin chains conjugated to Kenny by DIAP2. This suggests that DIAP2 and LUBEL work together to promote Kenny-mediated activation of Relish. We found LUBEL-mediated M1-Ub chain formation to be required for flies to survive oral infection with Gram-negative bacteria, for activation of Relish-mediated expression of antimicrobial peptide genes and for pathogen clearance during oral infection. Interestingly, LUBEL is not required for mounting an immune response against systemic infection, as Relish-mediated antimicrobial peptide genes can be expressed in the absence of LUBEL during septic injury. Finally, transgenic induction of LUBEL-mediated M1-Ub drives expression of antimicrobial peptide genes and hyperplasia in the midgut in the absence of infection. This suggests that M1-Ub chains are important for Imd signalling and immune responses in the intestinal epithelia, and that enhanced M1-Ub chain formation is able to drive chronic intestinal inflammation in flies.

dj-1ß regulates oxidative stress, insulin-like signaling and development in Drosophila melanogaster.

DJ-1 (or PARK-7) is a multifunctional protein implicated in numerous pathologies including cancer, sterility and Parkinson disease (PD). The popular genetic model Drosophila melanogaster has two orthologs, dj-1: α and ß. Dysfunction of dj-1ß strongly impairs fly mobility in an age-dependent manner. In this study, we analyze in detail the molecular mechanism underlying the dj-1ß mutant phenotype. Mitochondrial hydrogen peroxide production, but not superoxide production, was increased in mutant flies. An increase in peroxide leak from mitochondria causes oxidative damage elsewhere and explains the strong reduction in mobility caused by dj-1ß mutation. However, at the same time, increased levels of hydrogen peroxide activated a pro-survival program characterized by (1) an alteration in insulin-like signaling, (2) an increase in mitochondrial biogenesis and (3) an increase in the de-acetylase activity of sirtuins. The activation of this pro-survival program was associated with increased longevity under conditions of moderate oxidative stress. Additionally, the dj-1ß mutation unexpectedly accelerated development, a phenotype not previously associated with this mutation. Our results reveal an important role of dj-1ß in oxidative stress handling, insulin-like signaling and development in Drosophila melanogaster.