Structural and functional insights into GSDMB isoforms complex roles in pathogenesis

ABSTRACT SHADS

Gasdermins (GSDMs) have garnered significant scientific interest due to their protective and detrimental roles in innate immunity, host defense, inflammation, and cancer alongside with other pathologies. While GSDMs are mostly recognized as key effectors of a lytic type of pro-inflammatory cell death known as pyroptosis, they do also take part in other cell death processes (NETosis, secondary necrosis, or apoptosis) and exhibit cell-death independent functions depending on the cellular context. Among GSDMs, Gasdermin B (GSDMB) pyroptotic capacity has been a subject of conflicting findings in scientific literature even when its processing, and subsequent activation, by Granzyme A (GZMA) was decoded. Nevertheless, recent groundbreaking publications have shed light on the crucial role of alternative splicing in determining the pyroptotic capacity of GSDMB isoforms, which depends on the presence of exon 6-derived elements. This comprehensive review pays attention to the relevant structural differences among recently crystalized GSDMB isoforms. As a novelty, the structural aspects governing GSDMB isoform susceptibility to GZMA-mediated activation have been investigated. By elucidating the complex roles of GSDMB isoforms, this review aims to deepen the understanding of this multifunctional player and its potential implications in disease pathogenesis and therapeutic interventions.

KEYWORDS:

• Gasdermin
• alternative splicing
• pyroptosis
• cell death
• cancer
• inflammatory diseases

Acknowledgements

We are grateful to members of Gema Moreno-Bueno’s lab for constructive suggestions. SC, SO, PGP, DS and GMB belong to the Spanish National Research Council (CSIC) Cancer Hub.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors’ contributions

All authors wrote and revised the manuscript. DRP and PGP have carried out the structural and molecular dynamics techniques. SC and PGP made the figures.

Additional information

Funding

This study was financed by the following grants: Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (MICINN-AEI, PID2019-104644RB-I00, PDC2022-133252-I00, PID2022-136854OB-I00), the Instituto de Salud Carlos III (CIBERONC, CB16/12/00295), AC21_2/00020 ERA PerMed ERA-NET (cofunded by NextGenerationEU) and the AECC Scientific Foundation (FCAECC PROYE19036MOR and GCTRA18014MATI). DS contract is financed by CIBERONC (partly supported by FEDER funds). SC is funded by the MICINN-AEI PRE2020-095658.