Irgm1 coordinately regulates autoimmunity and host defense at select mucosal surfaces

Azzam, Kathleen M.; Madenspacher, Jennifer H.; Cain, Derek W.; Lai, Lihua; Gowdy, Kymberly M.; Rai, Prashant; Janardhan, Kyathanahalli S.; Clayton, Natasha P.; Cunningham, Willie; Jensen, Heather; Patel, Parit A.; Kearney, John F.; Taylor, Gregory A.; Fessler, Michael B.

doi:10.1172/jci.insight.91914

Cited by 21 publications

(24 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Immunity-related GTPase family M protein 1 (Irgm1), a member of a family of interferoninducible (IFN-inducible) cytoplasmic immunity-related GTPases required for mitochondrial homeostasis in B lymphocytes [27], was reduced in LPS stimulated TazKD B cells compared to WT B cells. Deficiency in Irgm1 is known to weaken the adaptive immune system and phagosome maturation and was reduced in LPS stimulated TazKD B cells compared to WT B cells.…”

Section: Taz-deficiency Reduces the Expression Of Surface Markers And Immunogenic Markers In Lps Stimulated B Cellsmentioning

confidence: 99%

Tafazzin regulates the function of lipopolysaccharide activated B lymphocytes in mice

Zegallai

Abu‐El‐Rub

Cole

et al. 2021

Preprint

View full text Add to dashboard Cite

B lymphocytes are responsible for humoral immunity and play a key role in the immune response. Optimal mitochondrial function is required to support B cell activity during activation. We examined how deficiency of tafazzin, a cardiolipin remodeling enzyme required for mitochondrial function, alters the metabolic activity of B cells and their response to activation by lipopolysaccharide in mice. B cells were isolated from 3 month old wild type or tafazzin knockdown mice and incubated for up to 72 h with lipopolysaccharide and cell proliferation, expression of cell surface markers, secretion of antibodies and chemokines, proteasome and immunoproteasome activities, and metabolic function determined. In addition, proteomic analysis was performed to identify altered levels of proteins involved in survival, immunogenic, proteasomal and mitochondrial processes. Compared to wild type lipopolysaccharide activated B cells, lipopolysaccharide activated tafazzin knockdown B cells exhibited significantly reduced proliferation, lowered expression of cluster of differentiation 86 and cluster of differentiation 69 surface markers, reduced secretion of immunoglobulin M antibody, reduced secretion of keratinocytes-derived chemokine and macrophage-inflammatory protein-2, reduced proteasome and immunoproteasome activities, and reduced mitochondrial respiration and glycolysis. Proteomic analysis revealed significant alterations in key protein targets that regulate cell survival, immunogenicity, proteasomal processing and mitochondrial function consistent with the findings of the above functional studies. The results indicate that the cardiolipin transacylase enzyme tafazzin plays a key role in regulating mouse B cell function and metabolic activity during activation.

show abstract

Section: Taz-deficiency Reduces the Expression Of Surface Markers And Immunogenic Markers In Lps Stimulated B Cellsmentioning

confidence: 99%

Tafazzin regulates the function of lipopolysaccharide activated B lymphocytes in mice

Zegallai

Abu‐El‐Rub

Cole

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The interferons thus produced can activate the JAK-STAT1/2 signaling pathway leading to the production of interferon-stimulated genes (ISGs), which are the powerful effector proteins with a varied function in innate immunity, including antiviral/antibacterial response (Ivashkiv & Donlin, 2014;Roers et al, 2016). The imbalance in all of these signaling pathways has been strongly linked with autoimmunity (Di Domizio & Cao, 2013;Rice et al, 2014;Gray et al, 2015;Kato & Fujita, 2015;Louis et al, 2018) IRGM (Irgm1) deficiency is genetically and functionally associated with several inflammatory and autoimmune diseases including ankylosing spondylitis, autoimmune thyroid diseases, Graves' disease, Sjogren's syndrome, Crohn's disease, experimental autoimmune encephalomyelitis, Hepatic steatosis, NAFLD (non-alcoholic fatty liver disease), and severe sepsis (Parkes et al, 2007;Xu et al, 2010;Kimura et al, 2014;Lin et al, 2016;Azzam et al, 2017;Bellini et al, 2017;Xia et al, 2017;Yao et al, 2018). Recently, in a knockout mouse model, Irgm1 (the mouse orthologue of IRGM) was shown to control autoimmunity (Azzam et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, in a knockout mouse model, Irgm1 (the mouse orthologue of IRGM) was shown to control autoimmunity (Azzam et al, 2017). The authors show that naive Irgm1 knockout mice, in germ-free conditions, displayed the hallmarks of Sjogren's syndrome, an autoimmune disorder characterized by lymphocytic infiltration of exocrine tissues (Azzam et al, 2017). The presence of IRGM/Irgm1 in humans and mice is shown to be largely protective against autoimmune disorders.…”

Section: Introductionmentioning

confidence: 99%

Autoimmunity gene IRGM suppresses cGAS ‐ STING and RIG ‐I‐ MAVS signaling to control interferon response

Jena¹,

Mehto

Nath³

et al. 2020

EMBO Reports

View full text Add to dashboard Cite

Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid‐sensing pathways leading to interferon‐stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG‐I, and mediates their p62‐dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS‐STING and RIG‐I‐MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.

show abstract

“…The interferons thus produced can activate the JAK-STAT1/2 signaling pathway leading to the production of interferon-stimulated genes (ISGs), which are the powerful effector proteins with a varied function in innate immunity, including antiviral/bacterial response (Ivashkiv and Donlin, 2014;Roers et al, 2016). The imbalance in all of these signaling pathways has been strongly linked with autoimmunity (Di Domizio and Cao, 2013;Gray et al, 2015;Kato and Fujita, 2015;Louis et al, 2018;Rice et al, 2014) IRGM (Irgm1) deficiency is genetically and functionally associated with several inflammatory and autoimmune diseases including ankylosing spondylitis, autoimmune thyroid diseases, Graves' disease, Sjogren's syndrome, Crohn's disease, experimental autoimmune encephalomyelitis, Hepatic steatosis, NAFLD (non-alcoholic fatty liver disease) and severe sepsis (Azzam et al, 2017;Bellini et al, 2017;Kimura et al, 2014;Lin et al, 2016;Parkes et al, 2007;Xia et al, 2017;Xu et al, 2010;Yao et al, 2018). Recently, in knock out mouse model, Irgm1 (mice orthologue of IRGM) was shown to control autoimmunity (Azzam et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, in knock out mouse model, Irgm1 (mice orthologue of IRGM) was shown to control autoimmunity (Azzam et al, 2017). They show that naive Irgm1 knock out mice in the germ-free conditions displayed the hallmarks of Sjogren's syndrome, an autoimmune disorder characterized by lymphocytic infiltration of exocrine tissues (Azzam et al, 2017). The presence of IRGM/Irgm1 in humans and mice is shown to be largely protective against autoimmune disorders.…”

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Irgm1 coordinately regulates autoimmunity and host defense at select mucosal surfaces

Cited by 21 publications

References 53 publications

Tafazzin regulates the function of lipopolysaccharide activated B lymphocytes in mice

Tafazzin regulates the function of lipopolysaccharide activated B lymphocytes in mice

Autoimmunity gene IRGM suppresses cGAS ‐ STING and RIG ‐I‐ MAVS signaling to control interferon response

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

Contact Info

Product

Resources

About