School of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW Sydney, Sydney, NSW, 2052, Australia.
School of Chemical Engineering, Faculty of Engineering, UNSW Sydney, Sydney, NSW, 2052, Australia.
Inflamm Res. 2022 Aug;71(7-8):785-795. doi: 10.1007/s00011-022-01595-x. Epub 2022 Jun 14.
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.
人类免疫相关 GTP 酶 M（IRGM）是一种 GTP 结合蛋白，可调节包括异噬作用和线粒体自噬在内的选择性自噬。IRGM 通过以下几种方式影响自噬：（1）影响线粒体融合和裂变；（2）促进 ULK1 和 Beclin 1 的共组装；（3）增强 Beclin 1 的相互作用伙伴（AMBRA1、ATG14L1 和 UVRAG）；（4）与其他关键蛋白（ATG16L1、p62、NOD2、cGAS、TLR3 和 RIG-I）相互作用；（5）调节溶酶体生物发生。IRGM 还负调控 NLRP3 炎性体的形成，从而影响重要促炎细胞因子 IL-1β的成熟，进而影响炎症和细胞焦亡。最终，这为慢性炎症性疾病提供了保护。重要的是，已有 10 个 IRGM 多态性（rs4859843、rs4859846、rs4958842、rs4958847、rs1000113、rs10051924、rs10065172、rs11747270、rs13361189 和 rs72553867）与人类炎症性疾病（包括癌症）相关，这表明这些遗传变异与自噬和炎症反应具有功能相关性。本综述从上下文角度介绍了 IRGM 及其对自噬和炎症的调节，并强调了 IRGM 作为免疫和肿瘤发生交叉点的作用。
