Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX, USA.
Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX, USA; MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, USA.
Cell Rep. 2021 Oct 26;37(4):109904. doi: 10.1016/j.celrep.2021.109904.
Inflammasomes are crucial for innate immunity against infections and, when deregulated, also contribute to inflammatory diseases. Here, we identify a critical function of the E3 ubiquitin ligase Peli1 in regulating the activation of NLRP3 inflammasome. Peli1 deficiency impairs induction of interleukin-1β (IL-1β) secretion by different NLRP3 inducers, but not by inducers of the Aim2, NLRP1, and NLRC4 inflammasomes. Peli1-deficient mice have alleviated peritonitis induction by alum and display increased resistance to lipopolysaccharide (LPS) endotoxin shock, coupled with decreased serum concentration of IL-1β. Peli1 is required for NLRP3-induced caspase-1 activation and IL-1β maturation. Mechanistically, Peli1 conjugates K63 ubiquitin chain to lysine 55 of the inflammasome adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which in turn facilitates ASC/NLRP3 interaction and ASC oligomerization, thereby contributing to inflammasome activation. Peli1 deficiency impairs the ubiquitination of ASC and inhibits inflammasome activation. Our findings establish Peli1 as an important inflammasome regulator and suggest a mechanism by which Peli1 mediates inflammatory responses.
炎症小体对于先天免疫对抗感染至关重要，而当其失调时，也会导致炎症性疾病。在这里，我们发现 E3 泛素连接酶 Peli1 在调节 NLRP3 炎症小体的激活方面具有关键作用。Peli1 缺陷会损害不同 NLRP3 诱导物诱导的白细胞介素-1β（IL-1β）分泌，但不会被 Aim2、NLRP1 和 NLRC4 炎症小体的诱导物所影响。Peli1 缺陷小鼠减轻了 alum 诱导的腹膜炎，并对脂多糖（LPS）内毒素休克表现出更高的抵抗力，同时血清中 IL-1β 的浓度降低。Peli1 是 NLRP3 诱导的半胱天冬酶-1 激活和 IL-1β 成熟所必需的。在机制上，Peli1 将 K63 泛素链连接到衔接蛋白凋亡相关斑点样蛋白（ASC）的赖氨酸 55 上，该蛋白反过来促进 ASC/NLRP3 相互作用和 ASC 寡聚化，从而有助于炎症小体的激活。Peli1 缺陷会损害 ASC 的泛素化并抑制炎症小体的激活。我们的研究结果确立了 Peli1 作为炎症小体调节因子的重要作用，并提出了 Peli1 介导炎症反应的机制。
