Review
Mechanisms of Gasdermin Family Members in Inflammasome Signaling and Cell Death

https://doi.org/10.1016/j.jmb.2018.07.002Get rights and content

Highlights

  • Gasdermins are a family of functionally diverse proteins with pore-forming potential.

  • Gasdermins, with the exception of Pejvakin, comprise a two-domain structure.

  • Certain gasdermins are cleaved by inflammatory and apoptotic caspases.

  • Gasdermin D has a central role in inflammasome signaling and pyroptosis.

  • Mutations in gasdermins are linked to inflammatory diseases and cancer.

Abstract

The Gasdermin (GSDM) family consists of Gasdermin A (GSDMA), Gasdermin B (GSDMB), Gasdermin C (GSDMC), Gasdermin D (GSDMD), Gasdermin E (GSDME) and Pejvakin (PJVK). GSDMD is activated by inflammasome-associated inflammatory caspases. Cleavage of GSDMD by human or mouse caspase-1, human caspase-4, human caspase-5, and mouse caspase-11 liberates the N-terminal effector domain from the C-terminal inhibitory domain. The N-terminal domain oligomerizes in the cell membrane and forms a pore of 10–16 nm in diameter, through which substrates of a smaller diameter, such as interleukin-1β and interleukin-18, are secreted. The increasing abundance of membrane pores ultimately leads to membrane rupture and pyroptosis, releasing the entire cellular content. Other than GSDMD, the N-terminal domain of all GSDMs, with the exception of PJVK, have the ability to form pores. There is evidence to suggest that GSDMB and GSDME are cleaved by apoptotic caspases. Here, we review the mechanistic functions of GSDM proteins with respect to their expression and signaling profile in the cell, with more focused discussions on inflammasome activation and cell death.

Introduction

Gasdermins (GSDMs) are a family of functionally diverse proteins which are expressed in a variety of cell types and tissues [1], [2], [3]. Earlier identification of GSDMs in the gastrointestinal tract and dermis led to its nomenclature, “gas-dermin” [4], [5]. Six GSDMs are found in humans and 10 GSDMs are found in mice. Humans carry genes encoding Gasdermin A (GSDMA; previously known as GSDM1) [4], [5], [6], Gasdermin B (GSDMB; gasdermin-like, GSDML, or PRO2521) [5], [7], Gasdermin C (GSDMC; melanoma-derived leucine zipper extranuclear factor, or MLZE) [5], [8], Gasdermin D (GSDMD; gasdermin domain-containing 1, GSDMDC1, deafness, autosomal dominant 5-like, or DFNA5L) [5], [9], Gasdermin E (GSDME or DFNA5) [10] and Pejvakin (PJVK, autosomal recessive deafness type 59, DFNB59, putative Gasdermin F, or GSDMF) [11] (Fig. 1).

Mice carry genes encoding three homologs of GSDMA (GSDMA1–3), four homologs of GSDMC (GSDMC1–4) and one homolog each of GSDMD, GSDME and PJVK [5]. Mice, however, do not carry a gene encoding GSDMB [5]. The presence of multiple copies of genes encoding the same GSDM member in mice likely arose during gene duplication events over the course of vertebrate evolution [5], [12] (Fig. 1). Some studies exclude GSDME and PJVK from the GSDM family based on their divergent expression pattern and mutant-associated phenotypes compared with other GSDM family members, despite similarities in gene sequences and structural arrangement of these two family members to other GSDMs [5].

An emerging function of GSDMs is their ability to induce cell death and inflammation, and, in particular, the role of GSDMD in inflammasome signaling and pyroptosis. An inflammasome is a cytosolic multimeric complex which activates the cysteine protease caspase-1 to drive proteolytic processing of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). The inflammasome also induces pyroptosis, a form of programmed cell death that is inflammatory due to the consequential release of IL-1β, IL-18 and danger signals (also known as danger-associated molecular patterns, or DAMPs), such as DNA, ATP and high mobility group box 1 (HMGB1), upon cell lysis [13]. Pyroptosis is characterized by cell swelling, nuclear condensation, disruption of the cell membrane, and release of inflammatory cytokines and DAMPs [14], [15]. The requirement of inflammatory caspases, namely, human and mouse caspase-1, human caspase-4 and caspase-5, and mouse caspase-11, to induce pyroptosis distinguishes pyroptosis from other forms of programmed cell death, such as apoptosis and necroptosis which do not rely on inflammatory caspases [13], [16], [17].

GSDMD is an executioner of pyroptosis owing to its ability to be cleaved by inflammatory caspases and its ability to form membrane pores [18], [19], [20], [21]. Although there is evidence to support the idea that the pore-forming ability of GSDMD may be conserved throughout the GSDM family [1], [18], the mechanisms of how other GSDMs form pores is largely unknown.

All GSDMs, with the exception of PJVK, comprise a conserved two-domain arrangement: a C-terminal domain and an N-terminal domain [18], [22], [23]. Full-length GSDM proteins do not normally induce cell death due to the presence of the C-terminal autoinhibitory domain binding to the N-terminal effector domain [1], [18], [23]. Once the C-terminal domain is removed via proteolytic cleavage, the N-terminal domain of certain GSDMs can bind to lipid components and form pores in the cell membrane [1], [18], [19], [24]. These GSDMs include GSDMA, GSDMA3, GSDMB, GSDMC, GSDMD and GSDME [18], [23], [25], [26], [27]. GSDMD induces pyroptosis following cleavage by inflammatory caspases [25], [28], [29], whereas the roles of GSDMs other than GSDMD in pyroptosis are less certain despite their N-terminal domains possessing pore-forming ability. There is some evidence to suggest that GSDME can induce cell death [26], [30], [31], [32], [33]. PJVK is homologous to the other GSDMs [11], but no information is available regarding its pore-forming function. In this review, we provide an overview of the latest advances in GSDM biology, with a focus on inflammasome signaling and cell death. We also discuss the expression profile and molecular regulation of GSDMs and highlight the importance of this protein family in human diseases.

Section snippets

Overview of Pattern-Recognition and Inflammasome Activation

The innate immune system functions as the first line of defense against microbial threats, requiring the concerted activity of germline-encoded pattern-recognition receptors (PRRs). PRRs detect pathogen-associated molecular patterns (PAMPs) found on pathogens or DAMPs in the form of endogenous self-molecules or foreign environmental irritants [34], [35], [36], [37]. PAMPs are structural motifs that are conserved among and characteristic of pathogens, enabling the host to differentiate between

Acknowledgments

S.F. was supported by a scholarship from the China Scholarship Council. S.M.M. is supported by the Australian National University, The Gretel and Gordon Bootes Medical Research Foundation and the National Health and Medical Research Council of Australia under Project grants (APP1141504 and APP1146864) and the R.G. Menzies Early Career Fellowship (APP1091544). The authors apologize to researchers whose work was not cited or cited through reviews owing to space limitation.

Competing Interests: The

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