1] National Institute of Biological Sciences, Beijing 102206, China [2].
1] National Institute of Biological Sciences, Beijing 102206, China [2] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [3].
Nature. 2014 Sep 11;513(7517):237-41. doi: 10.1038/nature13449. Epub 2014 Jun 11.
Cytosolic inflammasome complexes mediated by a pattern recognition receptor (PRR) defend against pathogen infection by activating caspase 1. Pyrin, a candidate PRR, can bind to the inflammasome adaptor ASC to form a caspase 1-activating complex. Mutations in the Pyrin-encoding gene, MEFV, cause a human autoinflammatory disease known as familial Mediterranean fever. Despite important roles in immunity and disease, the physiological function of Pyrin remains unknown. Here we show that Pyrin mediates caspase 1 inflammasome activation in response to Rho-glucosylation activity of cytotoxin TcdB, a major virulence factor of Clostridium difficile, which causes most cases of nosocomial diarrhoea. The glucosyltransferase-inactive TcdB mutant loses the inflammasome-stimulating activity. Other Rho-inactivating toxins, including FIC-domain adenylyltransferases (Vibrio parahaemolyticus VopS and Histophilus somni IbpA) and Clostridium botulinum ADP-ribosylating C3 toxin, can also biochemically activate the Pyrin inflammasome in their enzymatic activity-dependent manner. These toxins all target the Rho subfamily and modify a switch-I residue. We further demonstrate that Burkholderia cenocepacia inactivates RHOA by deamidating Asn 41, also in the switch-I region, and thereby triggers Pyrin inflammasome activation, both of which require the bacterial type VI secretion system (T6SS). Loss of the Pyrin inflammasome causes elevated intra-macrophage growth of B. cenocepacia and diminished lung inflammation in mice. Thus, Pyrin functions to sense pathogen modification and inactivation of Rho GTPases, representing a new paradigm in mammalian innate immunity.
细胞质炎性小体复合物通过模式识别受体 (PRR) 介导，通过激活半胱天冬酶 1 来抵御病原体感染。Pyrin，一种候选 PRR，可与炎性小体衔接蛋白 ASC 结合形成半胱天冬酶 1 激活复合物。编码 Pyrin 的基因 MEFV 中的突变导致一种称为家族性地中海热的人类自身炎症性疾病。尽管在免疫和疾病中发挥了重要作用，但 Pyrin 的生理功能仍然未知。在这里，我们表明 Pyrin 介导半胱天冬酶 1 炎性小体激活，以响应细胞毒素 TcdB 的 Rho 糖基化活性，TcdB 是艰难梭菌的主要毒力因子，引起大多数医院腹泻。无葡糖基转移酶活性的 TcdB 突变体失去了炎性小体刺激活性。其他 Rho 失活毒素，包括 FIC 结构域腺苷转移酶（副溶血弧菌 VopS 和豪氏霍尔氏菌 IbpA）和肉毒梭菌 ADP-核糖基化 C3 毒素，也可以通过其酶活性依赖性方式在生化上激活 Pyrin 炎性小体。这些毒素都靶向 Rho 亚家族并修饰开关-I 残基。我们进一步证明，伯克霍尔德菌中存在的一种半胱氨酸天冬氨酸蛋白酶 6 型分泌系统 (T6SS) 通过去酰胺化 switch-I 区域的 Asn41 使 RHOA 失活，从而触发 Pyrin 炎性小体激活，这两者都需要细菌的 T6SS。Pyrin 炎性小体的缺失导致 Burkholderia cenocepacia 在巨噬细胞内的过度生长和小鼠肺部炎症的减少。因此，Pyrin 作为一种感知病原体修饰和 Rho GTPase 失活的机制，代表了哺乳动物先天免疫的一个新范例。
