In recent years, our understanding of the mechanisms underlying colorectal carcinogenesis has vastly expanded. Underlying inflammation within the intestine, diet, and most recently, the gut ...microbiota, have been demonstrated to influence the development of colorectal cancer. However, since cancer is ultimately a genetic disease, these factors are thought to create genotoxic stress within the intestinal environment to promote genetic and epigenetic alterations leading to cancer. In this review, we will focus on how gut microbes intersect with inflammation, diet, and host genetics to influence the development of colon cancer.
Mitophagy pathways in health and disease Killackey, Samuel A; Philpott, Dana J; Girardin, Stephen E
The Journal of cell biology,
11/2020, Letnik:
219, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Mitophagy is an evolutionarily conserved process involving the autophagic targeting and clearance of mitochondria destined for removal. Recent insights into the complex nature of the overlapping ...pathways regulating mitophagy illustrate mitophagy's essential role in maintaining the health of the mitochondrial network. In this review, we highlight recent studies that have changed the way mitophagy is understood, from initiation through lysosomal degradation. We outline the numerous mitophagic receptors and triggers, with a focus on basal and physiologically relevant cues, offering insight into why they lead to mitochondrial removal. We also explore how mitophagy maintains mitochondrial homeostasis at the organ and system levels and how a loss of mitophagy may play a role in a diverse group of diseases, including cardiovascular, metabolic, and neurodegenerative diseases. With disrupted mitophagy affecting such a wide array of physiological processes, a deeper understanding of how to modulate mitophagy could provide avenues for numerous therapies.
The peptidoglycan sensor Nod2 and the autophagy protein ATG16L1 have been linked to Crohn’s disease (CD). Although Nod2 and the related sensor, Nod1, direct ATG16L1 to initiate anti-bacterial ...autophagy, whether ATG16L1 affects Nod-driven inflammation has not been examined. Here, we uncover an unanticipated autophagy-independent role for ATG16L1 in negatively regulating Nod-driven inflammatory responses. Knockdown of ATG16L1 expression, but not that of ATG5 or ATG9a, specifically enhanced Nod-driven cytokine production. In addition, autophagy-incompetent truncated forms of ATG16L1 regulated Nod-driven cytokine responses. Mechanistically, we demonstrated that ATG16L1 interfered with poly-ubiquitination of the Rip2 adaptor and recruitment of Rip2 into large signaling complexes. The CD-associated allele of ATG16L1 was impaired in its ability to regulate Nod-driven inflammatory responses. Overall, these results suggest that ATG16L1 is critical for Nod-dependent regulation of cytokine responses and that disruption of this Nod1- or Nod2-ATG16L1 signaling axis could contribute to the chronic inflammation associated with CD.
•ATG16L1 suppresses Nod1- and Nod2-driven cytokine responses•ATG16L1’s regulatory function is independent of its role in autophagosome formation•ATG16L1 negatively regulates Nod1 and Nod2 signaling via Rip2 activation•Crohn’s-disease-associated ATG16L1 allele is defective in Nod1 and Nod2 regulation
The etiology of colorectal cancer (CRC) has been linked to deficiencies in mismatch repair and adenomatous polyposis coli (APC) proteins, diet, inflammatory processes, and gut microbiota. However, ...the mechanism through which the microbiota synergizes with these etiologic factors to promote CRC is not clear. We report that altering the microbiota composition reduces CRC in APCMin/+MSH2−/− mice, and that a diet reduced in carbohydrates phenocopies this effect. Gut microbes did not induce CRC in these mice through an inflammatory response or the production of DNA mutagens but rather by providing carbohydrate-derived metabolites such as butyrate that fuel hyperproliferation of MSH2−/− colon epithelial cells. Further, we provide evidence that the mismatch repair pathway has a role in regulating β-catenin activity and modulating the differentiation of transit-amplifying cells in the colon. These data thereby provide an explanation for the interaction between microbiota, diet, and mismatch repair deficiency in CRC induction.
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•Gut microbiota induce colon cancer in genetically sensitized MSH2-deficient mice•Reduced dietary carbohydrates decreased polyp frequency in APCMin/+MSH2−/− mice•The carbohydrate metabolite butyrate induces colon cancer in APCMin/+MSH2−/− mice•MSH2 regulates β-catenin activity and/or transit-amplifying cell differentiation
Carbohydrate metabolites, produced by gut microbes, can directly induce hyperproliferation and transformation of genetically susceptible colon epithelial cells. This process is independent of inflammation or production of DNA mutagens and provides a mechanism for interaction of microbiota, diet, and mismatch repair deficiency in colorectal cancer induction.
Mammalian cell homeostasis during starvation depends on initiation of autophagy by endoplasmic reticulum-localized phosphatidylinositol 3-phosphate (PtdIns(3)P) synthesis. Formation of ...double-membrane autophagosomes that engulf cytosolic components requires the LC3-conjugating Atg12–5-16L1 complex. The molecular mechanisms of Atg12–5-16L1 recruitment and significance of PtdIns(3)P synthesis at autophagosome formation sites are unknown. By identifying interacting partners of WIPIs, WD-repeat PtdIns(3)P effector proteins, we found that Atg16L1 directly binds WIPI2b. Mutation experiments and ectopic localization of WIPI2b to plasma membrane show that WIPI2b is a PtdIns(3)P effector upstream of Atg16L1 and is required for LC3 conjugation and starvation-induced autophagy through recruitment of the Atg12–5-16L1 complex. Atg16L1 mutants, which do not bind WIPI2b but bind FIP200, cannot rescue starvation-induced autophagy in Atg16L1-deficient MEFs. WIPI2b is also required for autophagic clearance of pathogenic bacteria. WIPI2b binds the membrane surrounding Salmonella and recruits the Atg12–5-16L1 complex, initiating LC3 conjugation, autophagosomal membrane formation, and engulfment of Salmonella.
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•WIPI2 binds Atg16L1 directly and recruits the Atg12–5-16L1 complex•WIPI2 binding to Atg16L1 is required for LC3 lipidation and autophagosome formation•WIPI2-Atg16L1 function requires PI3P binding by WIPI2 and is independent of FIP200•Autophagosomal engulfment of Salmonella requires the WIPI2-Atg16L1 complex
Starvation-induced autophagy requires PtdIns(3)P locally produced on ER-derived membranes. Dooley et al. demonstrate that the PtdIns(3)P effector WIPI2b binds Atg16L1 to recruit Atg12–5-16L1 to PtdIns(3)P-positive omegasomes, resulting in LC3 lipidation and starvation-induced autophagy. These findings suggest that WIPI2b senses increases in PtdIns(3)P and directs LC3 conjugation to developing autophagosomes.
Autophagy, which targets cellular constituents for degradation, is normally inhibited in metabolically replete cells by the metabolic checkpoint kinase mTOR. Although autophagic degradation of ...invasive bacteria has emerged as a critical host defense mechanism, the signals that induce autophagy upon bacterial infection remain unclear. We find that infection of epithelial cells with Shigella and Salmonella triggers acute intracellular amino acid (AA) starvation due to host membrane damage. Pathogen-induced AA starvation caused downregulation of mTOR activity, resulting in the induction of autophagy. In Salmonella-infected cells, membrane integrity and cytosolic AA levels rapidly normalized, favoring mTOR reactivation at the surface of the Salmonella-containing vacuole and bacterial escape from autophagy. In addition, bacteria-induced AA starvation activated the GCN2 kinase, eukaryotic initiation factor 2α, and the transcription factor ATF3-dependent integrated stress response and transcriptional reprogramming. Thus, AA starvation induced by bacterial pathogens is sensed by the host to trigger protective innate immune and stress responses.
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► Intracellular bacteria trigger host amino acid (AA) starvation due to membrane damage ► AA starvation inhibits mTOR, which in-turn activates anti-bacterial autophagy ► Salmonella controls mTOR signaling to escape autophagy ► AA starvation activates GCN2-, eIF2α-, and ATF3-dependent responses
In this review, we present newly identified functions of HRI in innate immunity, proteostasis, and mitochondrial stress. Indeed, HRI‐mediated signaling defines a novel cytosolic unfolded protein ...response (cUPR) required for the proper formation of some innate immune signalosomes and the control of toxic protein aggregates, and this eIF2α kinase also serves as a relay for mitonuclear communication after a mitochondrial stress.
The integrated stress response (ISR) is an evolutionary conserved stress response pathway that leads to a global arrest in translation as well as to the expression of specific genes, such as the transcription factor ATF4, to promote cellular recovery. The central nexus of this pathway is the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) by one of the four eIF2α kinases that sense specific cellular stressors. The heme‐regulated inhibitor (HRI) is one of these kinases, and it was initially reported to be activated in response to heme deprivation. Nevertheless, further studies have established that cytosolic proteotoxicity, resulting from oxidative or osmotic stress, heat shock, and proteasome inhibition, is the predominant trigger for HRI to induce the ISR. In this review, we present newly identified functions of HRI in innate immunity, proteostasis, and mitochondrial stress. Indeed, HRI‐mediated signaling defines a novel cytosolic unfolded protein response (cUPR) required for the proper formation of some innate immune signalosomes and the control of toxic protein aggregates, and this eIF2α kinase also serves as a relay for mitonuclear communication after a mitochondrial stress.
Cells use mitophagy to remove damaged or unwanted mitochondria to maintain homeostasis. Here we report that the intracellular bacterial pathogen Listeria monocytogenes exploits host mitophagy to ...evade killing. We found that L. monocytogenes induced mitophagy in macrophages through the virulence factor listeriolysin O (LLO). We discovered that NLRX1, the only Nod-like receptor (NLR) family member with a mitochondrial targeting sequence, contains an LC3-interacting region (LIR) and directly associated with LC3 through the LIR. NLRX1 and its LIR motif were essential for L. monocytogenes-induced mitophagy. NLRX1 deficiency and use of a mitophagy inhibitor both increased mitochondrial production of reactive oxygen species and thereby suppressed the survival of L. monocytogenes. Mechanistically, L. monocytogenes and LLO induced oligomerization of NLRX1 to promote binding of its LIR motif to LC3 for induction of mitophagy. Our study identifies NLRX1 as a novel mitophagy receptor and discovers a previously unappreciated strategy used by pathogens to hijack a host cell homeostasis system for their survival.
IL- 1β and IL- 18 are pro-inflammatory cytokines that play a critical role in the response to a diverse array of injuries and infections. Accordingly, the production of these potent cytokines is ...tightly regulated at transcriptional and post-translational levels through control of both maturation and secretion.
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