Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), and remains a leading public health problem. Previous studies have identified host genetic factors that contribute to Mtb infection outcomes. However, much of the heritability in TB remains unaccounted for and additional susceptibility loci most likely exist. We perform a multistage genome-wide association study on 2949 pulmonary TB patients and 5090 healthy controls (833 cases and 1220 controls were genome-wide genotyped) from Han Chinese population. We discover two risk loci: 14q24.3 (rs12437118, Pcombined = 1.72 × 10−11, OR = 1.277, ESRRB) and 20p13 (rs6114027, Pcombined = 2.37 × 10−11, OR = 1.339, TGM6). Moreover, we determine that the rs6114027 risk allele is related to decreased TGM6 transcripts in PBMCs from pulmonary TB patients and severer pulmonary TB disease. Furthermore, we find that tgm6-deficient mice are more susceptible to Mtb infection. Our results provide new insights into the genetic etiology of TB.
Micronuclei are constantly considered as a marker of genome instability and very recently found to be a trigger of innate immune responses. An increased frequency of micronuclei is associated with many diseases, but the mechanism underlying the regulation of micronuclei homeostasis remains largely unknown. Here, we report that CGAS (cyclic GMP-AMP synthase), a known regulator of DNA sensing and DNA repair, reduces the abundance of micronuclei under genotoxic stress in an autophagy-dependent manner. CGAS accumulates in the autophagic machinery and directly interacts with MAP1LC3B/LC3B in a manner dependent upon its MAP1LC3-interacting region (LIR). Importantly, the interaction is essential for MAP1LC3 recruitment to micronuclei and subsequent clearance of micronuclei via autophagy (micronucleophagy) in response to genotoxic stress. Moreover, in contrast to its DNA sensing function to activate micronuclei-driven inflammation, CGAS-mediated micronucleophagy blunts the production of cyclic GMP-AMP (cGAMP) induced by genotoxic stress. We therefore conclude that CGAS is a receptor for the selective autophagic clearance of micronuclei and uncovered an unprecedented role of CGAS in micronuclei homeostasis to dampen innate immune surveillance.
Abbreviations:
ATG: autophagy-related; CGAS: cyclic GMP-AMP synthase; CQ: chloroquine; GABARAP: GABA type A receptor-associated protein; GFP: green fluorescent protein; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LIR, MAP1LC3-interacting region; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; NDZ: nocodazole; STING1: stimulator of interferon response cGAMP interactor 1
Excessive or uncontrolled release of proinflammatory cytokines caused by severe viral infections often results in host tissue injury or even death. Phospholipase C (PLC)s degrade phosphatidylinositol-4, 5-bisphosphate (PI(4,5)P2) lipids and regulate multiple cellular events. Here, we report that PLCβ2 inhibits the virus-induced expression of pro-inflammatory cytokines by interacting with and inhibiting transforming growth factor-β-activated kinase 1 (TAK1) activation. Mechanistically, PI(4,5)P2 lipids directly interact with TAK1 at W241 and N245, and promote its activation. Impairing of PI(4,5)P2’s binding affinity or mutation of PIP2-binding sites on TAK1 abolish its activation and the subsequent production of pro-inflammatory cytokines. Moreover, PLCβ2-deficient mice exhibit increased expression of proinflammatory cytokines and a higher frequency of death in response to virus infection, while the PLCβ2 activator, m-3M3FBS, protects mice from severe Coxsackie virus A 16 (CVA16) infection. Thus, our findings suggest that PLCβ2 negatively regulates virus-induced pro-inflammatory responses by inhibiting phosphoinositide-mediated activation of TAK1.
Objective
In this study, the association between preoperative levels of serum liver enzymes and overall survival (OS) was evaluated in patients with resectable pancreatic cancer.
Methods
Preoperative serum levels of alanine aminotransferase (ALT), aspartate aminotransferases (AST), γ-glutamyltransferase, alkaline phosphatase, and lactate dehydrogenase of 101 patients with pancreatic ductal adenocarcinoma (PDAC) were collected. Univariate and multivariate Cox hazard models were used to identify independent variables associated with OS in this cohort.
Results
Patients with elevated AST levels had significantly worse OS than patients with lower AST levels. A nomogram was created using TNM staging and AST levels and was shown to be more accurate in prediction than the American Joint Committee on Cancer 8th edition standard method.
Conclusion
Preoperative AST levels could be a novel independent prognostic biomarker for patients with PDAC. The incorporation of AST levels into a nomogram with TNM staging can be an accurate predictive model for OS in patients with resectable PDAC.
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