Pyroptotic executioner pore-forming protein GSDMD forms oligomeric assembly and exhibits amyloid-like attributes that could contribute for its pore-forming function.

IF 4.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemical Journal Pub Date : 2024-11-06 DOI:10.1042/BCJ20240416
Shamaita Chatterjee, Tarang Gupta, Gurvinder Kaur, Kausik Chattopadhyay
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Abstract

Gasdermin D (GSDMD) is the chief executioner of inflammatory cell death or pyroptosis. During pyroptosis, proteolytic processing of GSDMD releases its N-terminal domain (NTD), which then forms large oligomeric pores in the plasma membranes. Membrane pore-formation by NTD allows the release of inflammatory cytokines and causes membrane damage to induce cell death. Structural mechanisms of GSDMD-mediated membrane pore-formation have been extensively studied. However, less effort has been made to understand the physicochemical properties of GSDMD and their functional implications. Here, we explore detailed characterization of the physicochemical properties of mouse GSDMD (mGSDMD), and their implications in regulating the pore-forming function. Our study reveals that mGSDMD shows some of the hallmark features of amyloids, and forms oligomeric assemblies in solution that are critically dependent on the disulphide bond-forming ability of the protein. mGSDMD oligomeric assemblies do not resemble typical amyloid fibrils/aggregates, and do not show resistance to proteolytic degradation that is otherwise observed with the conventional amyloids. Our results further elucidate the essential role of an amyloid-prone region (APR) in the oligomerization and amyloid-like features of mGSDMD. Furthermore, alteration of this APR leads to compromised pore-forming ability and cell-killing activity of NTD released from mGSDMD. Taken together, our study for the first time provides crucial new insights regarding implications of the amyloid-like property of mGSDMD in regulating its pore-forming function, which is an essential requirement for this pyroptotic executioner. To the best of our knowledge, such mode of regulation of mGSDMD-function has not been appreciated so far.

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嗜火刽子手孔道形成蛋白 GSDMD 形成寡聚体集合体,并表现出淀粉样特性,这可能有助于其孔道形成功能。
Gasdermin D(GSDMD)是炎性细胞死亡或化脓作用的主要执行者。在化脓过程中,GSDMD 的蛋白水解过程会释放出其 N 端结构域(NTD),然后在质膜上形成大的寡聚孔。NTD 形成的膜孔可释放炎性细胞因子,并造成膜损伤,从而诱导细胞死亡。人们对 GSDMD 介导的膜孔形成的结构机制进行了广泛研究。然而,人们对 GSDMD 的理化性质及其功能影响的了解却较少。在此,我们探讨了小鼠 GSDMD(mGSDMD)理化性质的详细特征及其在调节孔形成功能方面的意义。我们的研究发现,mGSDMD 显示出淀粉样蛋白的一些标志性特征,并在溶液中形成寡聚体集合体,而这种集合体的形成主要依赖于蛋白质的二硫键形成能力。mGSDMD 寡聚体集合体与典型的淀粉样纤维/聚集体并不相似,也不像传统的淀粉样蛋白那样表现出抗蛋白水解降解的能力。我们的研究结果进一步阐明了淀粉样蛋白易形成区(APR)在 mGSDMD 的寡聚化和淀粉样特征中的重要作用。此外,APR的改变导致mGSDMD释放的NTD的孔形成能力和细胞杀伤活性受损。综上所述,我们的研究首次就 mGSDMD 的淀粉样特性在调节其孔隙形成功能方面的影响提供了至关重要的新见解,而孔隙形成功能是这种火性刽子手的基本要求。据我们所知,迄今为止还没有人了解过 mGSDMD 功能的这种调控模式。
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来源期刊
Biochemical Journal
Biochemical Journal 生物-生化与分子生物学
CiteScore
8.00
自引率
0.00%
发文量
255
审稿时长
1 months
期刊介绍: Exploring the molecular mechanisms that underpin key biological processes, the Biochemical Journal is a leading bioscience journal publishing high-impact scientific research papers and reviews on the latest advances and new mechanistic concepts in the fields of biochemistry, cellular biosciences and molecular biology. The Journal and its Editorial Board are committed to publishing work that provides a significant advance to current understanding or mechanistic insights; studies that go beyond observational work using in vitro and/or in vivo approaches are welcomed. Painless publishing: All papers undergo a rigorous peer review process; however, the Editorial Board is committed to ensuring that, if revisions are recommended, extra experiments not necessary to the paper will not be asked for. Areas covered in the journal include: Cell biology Chemical biology Energy processes Gene expression and regulation Mechanisms of disease Metabolism Molecular structure and function Plant biology Signalling
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