ABSTRACT
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.
Subject(s)
Autophagy/physiology , Carrier Proteins/physiology , Cytokines/biosynthesis , Nod1 Signaling Adaptor Protein/physiology , Nod2 Signaling Adaptor Protein/physiology , Animals , Autophagy-Related Protein 5 , Autophagy-Related Proteins , Carrier Proteins/chemistry , Carrier Proteins/genetics , Cell Line , Crohn Disease/genetics , Crohn Disease/immunology , Crohn Disease/pathology , Cytokines/genetics , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelial Cells/microbiology , Gene Expression Regulation , Gene Knockdown Techniques , Genetic Predisposition to Disease , Humans , Inflammation , Intestinal Mucosa/cytology , Mice , Microtubule-Associated Proteins/deficiency , Microtubule-Associated Proteins/physiology , Protein Processing, Post-Translational , RNA Interference , RNA, Small Interfering/pharmacology , Receptor-Interacting Protein Serine-Threonine Kinase 2 , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Signal Transduction , UbiquitinationABSTRACT
Lung cancer is one of the most commonly diagnosed cancers in Canada and a leading cause of cancer mortality. Lung cancer also affects First Nations, Inuit and Métis peoples significantly in Canada, which deserves further investigation as there is a literature gap on this topic. We sought to develop a deeper understanding of lung cancer diagnosis, incidence, mortality, and survival in First Nations, Inuit, and Métis peoples in Canada. A systematic search was conducted in bibliographic databases to identify relevant studies published between January 2000 and March 2023. Articles were screened and assessed for relevance using the Population/ Concept/ Context (PCC) framework. A total of 22 articles were included in the final analysis, of which 13 were Inuit-specific, 7 were First Nations-specific, and 2 were Métis-specific. The literature suggests that comparative incidence, mortality, and relative risk of lung cancer is higher and survival is poorer in First Nations, Inuit and Métis peoples. Lung cancer also has varying impact on these population depending on sex, age, location and other factors. This review illustrates that more comprehensive quantitative and qualitative lung cancer research is essential to further identify the structural causes for the high incidence of the disease.