Immunity-related GTPase IRGM at the intersection of autophagy, inflammation, and tumorigenesis

Abstract

The human immunity-related GTPase M (IRGM) is a GTP-binding protein that regulates selective autophagy including xenophagy and mitophagy. IRGM impacts autophagy by (1) affecting mitochondrial fusion and fission, (2) promoting the co-assembly of ULK1 and Beclin 1, (3) enhancing Beclin 1 interacting partners (AMBRA1, ATG14L1, and UVRAG), (4) interacting with other key proteins (ATG16L1, p62, NOD2, cGAS, TLR3, and RIG-I), and (5) regulating lysosomal biogenesis. IRGM also negatively regulates NLRP3 inflammasome formation and therefore, maturation of the important pro-inflammatory cytokine IL-1β, impacting inflammation and pyroptosis. Ultimately, this affords protection against chronic inflammatory diseases. Importantly, ten IRGM polymorphisms (rs4859843, rs4859846, rs4958842, rs4958847, rs1000113, rs10051924, rs10065172, rs11747270, rs13361189, and rs72553867) have been associated with human inflammatory disorders including cancer, which suggests that these genetic variants are functionally relevant to the autophagic and inflammatory responses. The current review contextualizes IRGM, its modulation of autophagy, and inflammation, and emphasizes the role of IRGM as a cross point of immunity and tumorigenesis.

Enhanced protein‐metabolite correlation analysis: To investigate the association between Staphylococcus aureus mastitis and metabolic immune pathways

“…47 Additionally, IRGM and IRF5 are recognized as pivotal regulators of immunity and inflammation. 48,49 Therefore, these specific proteins may play a crucial role in governing mammary immunity and its associated inflammatory response.…”

“…Tnfaip8l2 shows high expression levels in various tumor types and is considered a promising target for immunotherapy 47 . Additionally, IRGM and IRF5 are recognized as pivotal regulators of immunity and inflammation 48,49 . Therefore, these specific proteins may play a crucial role in governing mammary immunity and its associated inflammatory response.…”

Autophagy Dysregulation in Metabolic Associated Fatty Liver Disease: A New Therapeutic Target

“…The process for autophagy has three stages: initiation, maturation/nucleation, and degradation/expansion [ 39 , 40 ]. Various autophagy-related genes (ATG) proteins mediate this process.…”

“…IRGM controls the core autophagy machinery by interacting with NOD2 (nucleotide-binding oligomerization domain protein 2) and ATG16L1 [ 40 ]. IRGM stabilizes the Thr172 phosphorylated form of adenosine monophosphate-activated protein kinase (AMPK) [ 100 ], which is required for AMPK activation and the further phosphorylation of the ULK1 complex and Beclin-1 to induce autophagy [ 101 , 102 ].…”

“…IRGM stabilizes the Thr172 phosphorylated form of adenosine monophosphate-activated protein kinase (AMPK) [ 100 ], which is required for AMPK activation and the further phosphorylation of the ULK1 complex and Beclin-1 to induce autophagy [ 101 , 102 ]. IRGM are functionally relevant to inflammatory and autophagic responses [ 40 ]. Genetic susceptibility is a well-known factor for the risk of NAFLD [ 103 , 104 ].…”