{"doi":"10.1002/ctm2.787","title":"Live or let die: Translational insights and clinical perspectives of gasdermin B‐dependent intestinal epithelial cell fate","abstract":"Our group recently reported a critical role for the lipid-binding protein, gasdermin B (GSDMB), in intestinal wound healing,1 adding to a growing body of evidence indicating that GSDMB exerts important and multifaceted functions in intestinal epithelial cells (IECs). Notably, although it is well established that single-nucleotide polymorphisms (SNPs) in GSDMB are associated with susceptibility to several chronic inflammatory disorders, including inflammatory bowel disease (IBD),2, 3 less is known regarding the translational relevance of these genetic variations in a clinical setting. Indeed, recent studies are drawing increased attention to GSDMB in the field of gastroenterology because of its central role in colorectal cancer (CRC),4 enteric infections5 and IBD.1 The general concept of gasdermins is that they are expressed in full length (FL), inactive forms and, upon proteolytic activation, commonly mediated by a variety of proteases, their N-terminal (NT) fragments bind to the host's plasma membrane, wherein they assemble into pores that allow the flow of ions and small proteins, and can eventually lead to a form of lytic, programmed cell death, termed ‘pyroptosis’.6 Functional studies of GSDMB are hindered by the absence of a mouse ortholog6; however, recent work has emerged to clarify its role(s) in IECs. Importantly, Zhou et al. were the first to make the compelling observation that, in CRC cells, granzyme A, derived from tumour-resident natural killer and CD8+ T cells, is responsible for the proteolytic activation of GSDMB; in this model, GSDMB-mediated pyroptosis of neoplastic clones elicits tumour-suppressive responses within the tumour microenvironment.4 Hansen et al. confirm granzyme A-mediated proteolytic cleavage of epithelial-derived GSDMB in the context of enteric infection; however, they report specificity of GSDMB-NT pore assembly to the cell wall of invading Gram-negative bacteria that induces bacterial lysis, while sparing host IECs.5 Intriguingly, they also observe that the Gram-negative bacteria, Shigella flexneri, have evolved to evade this bactericidal function by a mechanism that involves proteasome-dependent clearance of GSDMB.5 One critical feature that distinguishes GSDMB from other gasdermin family members is its ability to bind lipid membranes, both in its FL form and as NT fragments.7 To date, there is no evidence to suggest that GSDMB-FL can form pores; however, our group describes a functional role for membrane-bound GSDMB-FL in IECs, independent of pyroptosis. Specifically, we show that in methotrexate (Mtx)-activated IECs, GSDMB-FL translocates to the plasma membrane, where it promotes epithelial restitution and repair by regulating cellular proliferation, migration and adhesion.8 These processes occur through a mechanism that is dependent on the homodimeric A chains of platelet-derived growth factor (PDGF-AA) that mediates phosphorylation of focal adhesion kinase (FAK), a key regulator of focal adhesions.8 Furthermore, we report the functional implications of two IBD-associated GSDMB SNPs, rs2305479 and rs2305480, showing that their presence impairs GSDMB-dependent epithelial restitution.1 Collectively, this body of work constitutes an interesting paradigm of GSDMB biology in IECs, based on three cornerstones. First, GSDMB expression is inducible in IECs and is upregulated in the context of inflammation and/or carcinogenesis. Second, the activation of particular GSDMB-dependent functions necessitates specific signals or events, often in cooperation with other gut mucosal cells and/or invading organisms. Third, GSDMB does not necessarily require cleavage to be active and can mediate either lytic or non-lytic functions. Indeed, it is possible that two different, dichotomous pathways for GSDMB activation exist: one producing NT fragments that form pores and mediate lytic cell death (of either human or bacterial cells), and the other relying on GSDMB-FL translocation to the plasma membrane that p","journal":"Clinical and Translational Medicine","year":2022,"id":289960,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9432,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":240325,"name":"Theresa T. Pizarro","orcid":"0000-0003-3163-915X","position":1,"is_corresponding":false},{"id":842123,"name":"Giuseppe Privitera","orcid":"0000-0002-7020-5808","position":0,"is_corresponding":true}],"reference_count":20,"raw_metadata":null,"created_at":"2026-07-19T00:30:26.667578Z","pmid":"35485236","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}