bims-inflin 2025-03-30 papers

EMBO J. 2025 Mar 24.

A bacterial network of T3SS effectors counteracts host pro-inflammatory responses and cell death to promote infection.

Hui Wen Yeap, Ghin Ray Goh, Safwah Nasuha Rosli, Hai Shin Pung, Cristina Giogha, Vik Ven Eng, Jaclyn S Pearson, Elizabeth L Hartland, Kaiwen W Chen.

Innate immune signalling and cell death pathways are highly interconnected processes involving receptor-interacting protein kinases (RIPKs) as mediators of potent anti-microbial responses. However, these processes are often antagonised by bacterial type III secretion system (T3SS) effectors, and the cellular mechanisms by which the host retaliates are not completely understood. Here, we demonstrate that during Citrobacter rodentium infection, murine macrophages and colonic epithelial cells exhibit RIPK1 kinase-dependent caspase-8 activation to counteract NleE effector-mediated suppression of pro-inflammatory signalling. While C. rodentium injects into the host cells a second effector, NleB, to block caspase-8 signalling, macrophages respond by triggering RIPK3-mediated necroptosis, whereupon a third T3SS effector, EspL, acts to inactivate necroptosis. We further show that NleB and EspL collaborate to suppress caspase-8 and NLRP3 inflammasome activation in macrophages. Our findings suggest that C. rodentium has evolved to express a complex network of effectors as an adaptation to the importance of cell death for anti-bacterial defence in the host-pathogen arms race.

Keywords: Apoptosis; Caspase-8; Infection; Necroptosis; Pyroptosis

DOI: https://doi.org/10.1038/s44318-025-00412-5

Trends Cell Biol. 2025 Mar 21. pii: S0962-8924(25)00061-3. [Epub ahead of print]

Versatility of gasdermin D beyond pyroptosis.

Tianming Zhao, Zhexu Chi, Di Wang.

Gasdermin D (GSDMD) has garnered significant attention primarily for the pore-forming role of its p30 N-terminal fragment (NT-p30) generated during pyroptosis, a proinflammatory form of cell death. However, emerging evidence suggests that the formation of GSDMD-NT pores is reversible, and the activation of GSDMD does not necessarily lead to pyroptosis. Instead, this process may take part either in other forms of cell death, or in various state changes of living cells, including (i) inflammation regulation, (ii) endolysosomal pathway rewiring, (iii) granule exocytosis, (iv) type II immunity, (v) food tolerance maintenance, and (vi) temporary permeability alteration. This review explores the latest insights into the involvement of GSDMD in cell death and homeostasis maintenance, aiming to underscore the pleiotropic nature of GSDMD.

Keywords: cell death; gasdermin D; homeostasis; pyroptosis

DOI: https://doi.org/10.1016/j.tcb.2025.02.011

Autophagy. 2025 Mar 26.

Staphylococcus aureus reprograms CASP8 (caspase 8) signaling to evade cell death and Xenophagy.

Yi-Tian Ying, Jing Yang, Hui-Wen Ye, Mei-Yi Chen, Xia Liu, Wei Chen, Jin-Xin Xu, Xun Tan.

Regulated cell death and xenophagy constitute fundamental cellular mechanisms against invading microorganisms. Staphylococcus aureus, a notorious pathogen, can invade and persist within host cells for extended periods. Here, we describe a novel mechanism by which S. aureus subverts these host defenses through the manipulation of the CASP8 (caspase 8) signaling pathway. Upon invasion, S. aureus triggers the assembly of a RIPK3 (receptor interacting serine/threonine kinase 3) complex to induce CASP8 autoprocessing. However, the bacterium inhibits CUL3 (cullin 3)-dependent K63-linked ubiquitination, leading to an atypical activation of CASP8. This non-canonical activation does not initiate the CASP8-CASP3 cascade but instead suppresses RIPK3-dependent necroptosis, a regulated cell death pathway typically activated when apoptosis fails. The resulting non-apoptotic, cleaved CASP8 redirects its enzymatic activity toward cleaving SQSTM1/p62, a selective macroautophagy/autophagy receptor, thus enabling S. aureus to evade antimicrobial xenophagy. The results of this study suggest that S. aureus reprograms the CASP8 signaling pathway from inducing cell death to preserving cell survival and inhibiting xenophagy, a critical strategy that supports its stealthy replication and persistence within host cells.

Keywords: Apoptosis; RIPK1; RIPK3; SQSTM1/p62; autophagy; necroptosis

DOI: https://doi.org/10.1080/15548627.2025.2483887

Nat Rev Mol Cell Biol. 2025 Mar 24.

Mechanistic insights into gasdermin-mediated pyroptosis.

Yang Bai, Youdong Pan, Xing Liu.

Pyroptosis, a novel mode of inflammatory cell death, is executed by membrane pore-forming gasdermin (GSDM) family members in response to extracellular or intracellular injury cues and is characterized by a ballooning cell morphology, plasma membrane rupture and the release of inflammatory mediators such as interleukin-1β (IL-1β), IL-18 and high mobility group protein B1 (HMGB1). It is a key effector mechanism for host immune defence and surveillance against invading pathogens and aberrant cancerous cells, and contributes to the onset and pathogenesis of inflammatory and autoimmune diseases. Manipulating the pore-forming activity of GSDMs and pyroptosis could lead to novel therapeutic strategies. In this Review, we discuss the current knowledge regarding how GSDM-mediated pyroptosis is initiated, executed and regulated, its roles in physiological and pathological processes, and the crosstalk between different modes of programmed cell death. We also highlight the development of drugs that target pyroptotic pathways for disease treatment.

DOI: https://doi.org/10.1038/s41580-025-00837-0