The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy

Mehto, Subhash; Jena, Kautilya Kumar; Nath, Parej; Chauhan, Swati; Kolapalli, Srinivasa Prasad; Das, Saroj Kumar; Sahoo, Pradyumna Kumar; Jain, Ashish; Taylor, Gregory A.; Chauhan, Santosh

doi:10.1016/j.molcel.2018.11.018

Cited by 166 publications

(188 citation statements)

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“…Activations of these pathways lead to robust induction of interferon response resulting in antiviral response or autoimmune diseases (Gkirtzimanaki et al, 2018;Sliter et al, 2018;Tal et al, 2009;Xu et al, 2019). Others and we have found that IRGM is a key autophagy protein that plays a significant role in anti-bacterial autophagy and autophagy of inflammasomes (Chauhan et al, 2015;Kumar et al, 2018;Mehto et al, 2019;Singh et al, 2006;Singh et al, 2010). IRGM was also shown to present over mitochondria, and overexpression of IRGM induces mitochondrial fission, followed by its depolarization (Singh et al, 2010).…”

Section: Introductionmentioning

confidence: 81%

“…The endogenous levels of RIG-I, cGAS, and TLR3 (but not of TLR4 and MAVS) were reduced by stable (HT-29 cells) or transient (THP1 cells) overexpression (for 4 hrs) of Flag-IRGM (Figure 3E and 3F). Previously, we have shown that IRGM does not affect the expression levels of NLRC4 and AIM2 (Mehto et al, 2019). Since cGAS, RIG-I, and TLR3 expression is controlled by IFN response, the reduction of endogenous levels of these proteins could be an indirect effect of IRGM-mediated suppression of IFN response.…”

Section: Irgm Interacts and Degrades Nucleic Acid Sensor Proteins Tomentioning

confidence: 90%

“…In the absence of external stimuli, the endogenous DAMPs from dysfunctional mitochondria are the major triggers for the type 1 IFN response (Angajala et al, 2018;West et al, 2015;Zhang et al, 2010). We and others have shown that depletion of IRGM in human cells or mice results in defective autophagy (Dong et al, 2015;He et al, 2012;Mehto et al, 2019) ( Supplementary Figure 5A and 5B) and this can result in impaired mitophagy and accumulation of defunct mitochondria. Indeed, we observed a significantly higher number of fused, swollen, and clumped mitochondria in Irgm1 -/-BMDMs and IRGM siRNA knockdown cells (Figure 5A-5D).…”

Section: Irgm Mediates P62-dependent Autophagic Degradation Of Nucleimentioning

confidence: 93%

“…IRGM facilitates the autophagic degradation of proteins. However itself, it is not degraded by autophagy (Kumar et al, 2018;Mehto et al, 2019). This is not surprising as several of the core autophagy proteins such as ULK1, ATG16L1, ATG12 (Haller et al, 2014;Nazio et al, 2016;Scrivo et al, 2019) and endolysosomal trafficking proteins such as RAB7A (Mohapatra et al, 2019), which facilitates autophagic degradation of cargo proteins but themselves are not degraded by the autophagy.…”

Section: Irgm Mediates P62-dependent Autophagic Degradation Of Nucleimentioning

confidence: 99%

“…IRGM is an autophagy protein, and its deficiency leads to diminished autophagy flux in immune cells (Chauhan et al, 2015;Dong et al, 2015;Hansen et al, 2017;Kumar et al, 2018;Mehto et al, 2019;Singh et al, 2006). IRGM is known to interact and degrade several PRRs, including NOD1, NOD2, and NLRP3 (Chauhan et al, 2015;Mehto et al, 2019). The PRR's are the threat sensor proteins, which commits the pathways for cytokines response.…”

Section: Irgm Interacts and Degrades Nucleic Acid Sensor Proteins Tomentioning

confidence: 99%

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Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways

Mehto

Nath

et al. 2019

Preprint

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Activation of type 1 interferon response is extensively connected with the antiviral immunity and pathogenesis of autoimmune diseases. Here, we found that IRGM, whose deficiency is linked with the genesis of several autoimmune disorders, is a master negative regulator of the interferon response. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their autophagic degradation to restrain activation of interferon signaling. Further, IRGM maintains mitophagy flux, and its deficiency results in the accumulation of defunct leaky mitochondria that releases cytosolic DAMPs triggering activation of interferon responses via cGAS-STING and RIG-I-MAVS signaling axis. Due to an enduring type 1 IFN response in IRGM-deficient cells and mice, they were intrinsically resistant to infection of the Japanese Encephalitis virus, Herpes Simplex virus, and Chikungunya virus. Altogether, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases. Further, it identifies IRGM as a broad therapeutic target for defense against viruses.

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Section: Introductionmentioning

confidence: 81%

Section: Irgm Interacts and Degrades Nucleic Acid Sensor Proteins Tomentioning

confidence: 90%

Section: Irgm Mediates P62-dependent Autophagic Degradation Of Nucleimentioning

confidence: 93%

Section: Irgm Mediates P62-dependent Autophagic Degradation Of Nucleimentioning

confidence: 99%

Section: Irgm Interacts and Degrades Nucleic Acid Sensor Proteins Tomentioning

confidence: 99%

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Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways

Mehto

Nath

et al. 2019

Preprint

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Paneth cells and their multiple functions

Barreto

Rattes

Costa

et al. 2022

Cell Biology International

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The small intestine mucosa is lined by specialized cells that form the crypt-villus axis, which expands its surface. Among the six intestinal epithelial cell types, the Paneth cell is located at the base of the crypt, and it contains numerous granules in its cytoplasm, composed of antimicrobial peptides, such as defensins and lysozyme, and growth factors, such as epidermal growth factor, transforming growth factor-α, and Wnt ligands. Together, these elements act in the defense against microorganisms, regulation of intestinal microbiota, maintenance, and regulation of stem cell identity.Pathologies that target Paneth cells can disturb such defense activity, but they also affect the maintenance of the stem cell niche. In that way, Crohn's disease, necrotizing enterocolitis, and graft-versus-host disease promote a reduction of Paneth cell population, and, consequently, secretion of their products into the lumen of the crypts, making the affected organism predisposed to infections and dysbiosis. Additionally, the emergence of new intestinal cells is also decreased. This review aims to address the main characteristics of Paneth cells, highlighting their multiple functions and the importance of their preservation to ensure bowel homeostasis.

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Autophagy and immunological aberrations in systemic lupus erythematosus

Zhou

Zhang

2019

Eur J Immunol

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease, in which immune defects can occur at multiple points of the cascading auto‐aggressive immune reactions, resulting in a striking heterogeneity of clinical presentations. The clinical manifestations of such autoimmune response can be severe: common manifestations symptoms include rash and renal inflammation progressing to kidney failure. Autophagy, the cellular “self‐digestion” process, is a key factor in the interplay between innate and adaptive immunity. Dysregulation of autophagy has been implicated in numerous autoimmune diseases. Several lines of evidence from genomic studies, cell culture systems, animal models, and human patients are emerging to support the role of autophagy in progression and pathogenesis of SLE. In this review, we summarize recent key findings on the aberrations of autophagy in SLE, with a special focus on how deregulated autophagy promotes autoimmunity and renal damage. We will also discuss how the observed findings may be translated into therapeutic settings.

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The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy

Cited by 166 publications

References 51 publications

Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways

Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways

Paneth cells and their multiple functions

Autophagy and immunological aberrations in systemic lupus erythematosus

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