小柯机器人

美国埃默里医学院Christopher N. LaRock的研究显示在角质形成细胞中A型链球菌(GAS)诱导了GSDMA依赖性焦亡。相关论文于2022年5月11日发表于国际学术期刊《自然》杂志。

在本研究中，研究人员发现主要的人类病原体A链球菌可分泌一种蛋白酶毒力因子 SpeB，从而诱导GSDMA依赖性细胞焦亡。GSDMA被SpeB水解后会释放一个活性氨基末端片段，该片段可以插入膜中形成裂解孔。GSDMA主要在皮肤中表达，GAS感染的角质形成细胞死于GSDMA依赖性细胞焦亡。小鼠中存在人GSDMA的三个同源物，敲除这三个基因的小鼠更容易受到GAS流行性、高毒性M1T1克隆的侵袭性感染。这些结果表明GSDMA在应对GAS侵袭性皮肤感染免疫防御中发挥重要功能。

此外，研究还表明GSDM可以独立于宿主调节器而作为外源蛋白酶的直接传感器。由于SpeB对GAS在皮肤组织侵袭和存活至关重要，这些结果表明GSDMA可以起到类似于保护蛋白的作用，可用于直接检测严重感染时微生物的毒力活动。

据了解，Gasdermins (GSDMs) 隶属于穿孔效应子家族，在细胞焦亡过程中破坏细胞膜。GSDM通过蛋白水解去除其自身抑制性羧基末端结构域而激活，而这一过程通常是由半胱天冬酶调节因子完成。然而，缺乏该家族成员GSDMA的激活因子。

附：英文原文

Title: Group A Streptococcus induces GSDMA-dependent pyroptosis in keratinocytes

Author: LaRock, Doris L., Johnson, Anders F., Wilde, Shyra, Sands, Jenna S., Monteiro, Marcos P., LaRock, Christopher N.

Issue&Volume: 2022-05-11

Abstract: Gasdermins (GSDMs) are a family of pore-forming effectors that permeabilize the cell membrane during the cell death program pyroptosis1. GSDMs are activated by proteolytic removal of autoinhibitory carboxy-terminal domains, typically by caspase regulators1,2,3,4,5,6,7,8,9. However, no activator is known for one member of this family, GSDMA. Here we show that the major human pathogen group A Streptococcus (GAS) secretes a protease virulence factor, SpeB, that induces GSDMA-dependent pyroptosis. SpeB cleavage of GSDMA releases an active amino-terminal fragment that can insert into membranes to form lytic pores. GSDMA is primarily expressed in the skin10, and keratinocytes infected with SpeB-expressing GAS die of GSDMA-dependent pyroptosis. Mice have three homologues of human GSDMA, and triple-knockout mice are more susceptible to invasive infection by a pandemic hypervirulent M1T1 clone of GAS. These results indicate that GSDMA is critical in the immune defence against invasive skin infections by GAS. Furthermore, they show that GSDMs can act independently of host regulators as direct sensors of exogenous proteases. As SpeB is essential for tissue invasion and survival within skin cells, these results suggest that GSDMA can act akin to a guard protein that directly detects concerning virulence activities of microorganisms that present a severe infectious threat.

DOI: 10.1038/s41586-022-04717-x

Source: https://www.nature.com/articles/s41586-022-04717-x

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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