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, Volume:
219, Issue:
11
Journal Article
Peer reviewed
Open access
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.
Innate immunity confers an immediate nonspecific mechanism of microbial recognition through germ line-encoded pattern recognition receptors (PRRs). Of these, Toll-like receptors (TLRs) and ...nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) have shaped our current understanding of innate regulation of adaptive immunity. It is now recognized that PRRs are paramount in instructing an appropriate adaptive immune response. Their ligands have been the focus of adjuvant research with the goal of generating modern vaccine combinations tailored to specific pathogens. In this review we will highlight the recent findings in the field of adjuvant research with a particular focus on the potential of TLR and NLR ligands as adjuvants and their influence on adaptive immune responses.
Nucleotide binding oligomerization domain (NOD)-like receptors are cytoplasmic pattern-recognition receptors that together with RIG-I-like receptor (retinoic acid-inducible gene 1), Toll-like ...receptor (TLR), and C-type lectin families make up the innate pathogen pattern recognition system. There are 22 members of NLRs in humans, 34 in mice, and even a larger number in some invertebrates like sea urchins, which contain more than 200 receptors. Although initially described to respond to intracellular pathogens, NLRs have been shown to play important roles in distinct biological processes ranging from regulation of antigen presentation, sensing metabolic changes in the cell, modulation of inflammation, embryo development, cell death, and differentiation of the adaptive immune response. The diversity among NLR receptors is derived from ligand specificity conferred by the leucine-rich repeats and an NH2-terminal effector domain that triggers the activation of different biological pathways. Here, we describe NLR genes associated with different biological processes and the molecular mechanisms underlying their function. Furthermore, we discuss mutations in NLR genes that have been associated with human diseases.
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 aetiology and pathogenesis of inflammatory bowel disease (IBD) remains unclear but involves a complex interplay between genetic risk, environmental exposures, the immune system and the gut ...microbiota. Nearly two decades ago, the first susceptibility gene for Crohn's disease, NOD2, was identified within the IBD 1 locus. Since then, over 230 genetic risk loci have been associated with IBD and yet NOD2 remains the strongest association to date. As an intracellular innate immune sensor of bacteria, investigations into host–microbe interactions, involving both innate and adaptive immune responses, have become of particular interest in understanding the pathogenesis of IBD. Advancements in sequencing technology have lead to the groundbreaking characterization of the gut microbiota and its role in health and disease. While an altered microbiome has been described for IBD, whether it is a cause or an effect of the intestinal inflammation has yet to be determined. Moreover, the bidirectional relationship between the gut microbiota and the mucosal immune system adds to the multifaceted complexity of intestinal homeostasis. A better understanding of how host genetics, including NOD2, influence immune–microbe interactions and alter susceptibility to IBD is necessary in order to develop therapeutic and preventative treatments.
The multi‐factorial etiology of IBD. Genetically susceptible individuals may experience some form of environmental trigger that induces an immune response against gut microbiota. The uncontrolled immune activation is thought to initiate disease or result in a flare.
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.
Entry of bacteria into host cells is an important virulence mechanism. Through peptidoglycan recognition, the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 enable detection ...of intracellular bacteria and promote their clearance through initiation of a pro-inflammatory transcriptional programme and other host defence pathways, including autophagy. Recent findings have expanded the scope of the cellular compartments monitored by NOD1 and NOD2 and have elucidated the signalling pathways that are triggered downstream of NOD activation. In vivo, NOD1 and NOD2 have complex roles, both during bacterial infection and at homeostasis. The association of alleles that encode constitutively active or constitutively inactive forms of NOD2 with different diseases highlights this complexity and indicates that a balanced level of NOD signalling is crucial for the maintenance of immune homeostasis.
A gut bacterial strain rescues stunted growth Yadav, Jitender; Philpott, Dana J
Science (American Association for the Advancement of Science),
02/2023, Volume:
379, Issue:
6634
Journal Article
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