Py Bénédicte F, Jin Mingzhi, Desai Bimal N, Penumaka Anirudh, Zhu Hong, Kober Maike, Dietrich Alexander, Lipinski Marta M, Henry Thomas, Clapham David E, Yuan Junying
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; International Center for Infectiology Research, INSERM U1111, CNRS UMR5308, École Normale Supérieure de Lyon, Claude Bernard Lyon 1 University, 69007 Lyon, France.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell Rep. 2014 Mar 27;6(6):1122-1128. doi: 10.1016/j.celrep.2014.02.015. Epub 2014 Mar 13.
Caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1β (IL-1β) secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide (LPS) and Gram-negative bacteria. However, we still know very little about the downstream mechanism of caspase-11 in regulating inflammation because the known substrates of caspase-11 are only other caspases. Here, we identify the cationic channel subunit transient receptor potential channel 1 (TRPC1) as a substrate of caspase-11. TRPC1 deficiency increases the secretion of IL-1β without modulating caspase-1 cleavage or cell death in cultured macrophages. Consistently, trpc1(-/-) mice show higher IL-1β secretion in the sepsis model of intraperitoneal LPS injection. Altogether, our data suggest that caspase-11 modulates the cationic channel composition of the cell and thus regulates the unconventional secretion pathway in a manner independent of caspase-1.
半胱天冬酶 -11是一种高度可诱导的半胱天冬酶，可控制炎症反应和细胞死亡。半胱天冬酶 -11通过增强半胱天冬酶 -1的激活来控制白细胞介素1β（IL-1β）的分泌，并在非经典NLRP3炎性小体激活剂（如脂多糖（LPS）和革兰氏阴性菌）下游诱导不依赖半胱天冬酶 -1的细胞焦亡。然而，我们对半胱天冬酶 -11调节炎症的下游机制仍然知之甚少，因为已知的半胱天冬酶 -11底物只有其他半胱天冬酶。在这里，我们确定阳离子通道亚基瞬时受体电位通道1（TRPC1）是半胱天冬酶 -11的底物。TRPC1缺陷会增加IL-1β的分泌，而不会调节培养巨噬细胞中半胱天冬酶 -1的切割或细胞死亡。同样，在腹腔注射LPS的脓毒症模型中，trpc1（-/-）小鼠表现出更高的IL-1β分泌。总之，我们的数据表明，半胱天冬酶 -11调节细胞的阳离子通道组成，从而以独立于半胱天冬酶 -1的方式调节非常规分泌途径。
