bims-cediti 2025-09-21 papers

bims-cediti

Biomed News

on Cell death in innate immunity, inflammation, and tissue repair

Issue of 2025–09–21
six papers selected by
Kateryna Shkarina, Universität Bonn

From Pores to Rupture: Structural Basis and Regulation of Lytic Cell Death by Gasdermins and NINJ1.
Intercellular propagation of RIPK1/RIPK3 amyloid fibrils.
Pathogenic phosphorylation of linear ubiquitin machinery causes inflammasome sensor degradation.
Innate detection of Salmonella replication triggers caspase-8-dependent apoptosis via TLR-driven TNF signaling and NLRC4-mediated sensing of the SPI-2 Type III secretion system.
A dominant role of cell death in limiting Chandipura virus propagation at cell-saturating high multiplicity of infection.
Myeloperoxidase transforms chromatin into neutrophil extracellular traps.

J Biol Chem. 2025 Sep 12. pii: S0021-9258(25)02550-5. [Epub ahead of print] 110698

From Pores to Rupture: Structural Basis and Regulation of Lytic Cell Death by Gasdermins and NINJ1.

Chengliang Wang, Brooke Dreyer, Evelyn Teran, Jianbin Ruan.

  Gasdermins (GSDMs) are a family of pore-forming proteins that execute lytic cell death by forming large β-barrel pores in cellular membranes. While traditionally regarded as the terminal effectors of pyroptosis, recent advances have revealed that GSDM pores alone are insufficient to cause full plasma membrane rupture, prompting the identification of NINJ1 as a critical executor of terminal cell lysis. This review provides an in-depth overview of the structural basis of GSDM pore formation and the regulatory mechanisms that govern their activity, including diverse post-translational modifications such as ubiquitination, palmitoylation, and PARylation. We also expand our discussion to the non-canonical activation strategies observed in bacterial, fungal, and ancient eukaryotic GSDM homologs. We further explore the molecular mechanisms for NINJ1 activation, highlighting its global role in mediating plasma membrane rupture downstream of multiple lytic cell death pathways. Finally, we discuss the pathological implications of dysregulated NINJ1 activity in related diseases, emphasizing its therapeutic potential as a universal modulator of terminal cell rupture.

Keywords:  GSDM; NINJ1; Ninjurin 1; gasdermin; membrane rupture; necrosis; pyroptosis

DOI:  https://doi.org/10.1016/j.jbc.2025.110698
Proc Natl Acad Sci U S A. 2025 Sep 23. 122(38): e2507028122

Intercellular propagation of RIPK1/RIPK3 amyloid fibrils.

Yeyang Ma, Qiuyuan Zhang, Dekang Li, Kun Zhao, Zefei Li, Yuan Liu, Chu Wang, Bo Sun, Dan Li, Junying Yuan, Cong Liu.

  The canonical necrosome formed by receptor-interacting protein kinase 1 (RIPK1) and RIPK3 is a functional amyloid fibril structure critical to intracellularly drive necroptosis. Since necroptosis leads to the release of intracellular content, the fate of RIPK1/RIPK3 fibrils after necroptotic cell death has not been investigated. Here, we tracked RIPK1 and RIPK3 coassemblies and found that these fibrillar aggregates could be released into the culture medium after the membrane rupture in necroptotic cells. Interestingly, these RIPK1/RIPK3 fibrils were capable of infiltrating recipient cells and acting as seeds for the nucleation and formation of the endogenous necrosome. Cryo electron microscopy structural analysis unveiled a distinctive S-shaped conformation common to RHIM fibrils of RIPK1 and RIPK3, which can facilitate the cross-seeding of RIPK3 by RIPK1 or RIPK1/RIPK3 fibrils. Our findings suggest the ability of functional RIPK1/RIPK3 amyloid fibrils in intercellular spreading to induce protein conformation change in recipient cells and provide structural insights into the mechanism of RIPK1 and RIPK3 cross-templating to drive necroptosis.

Keywords:  RIPK1; RIPK3; amyloid; necroptosis; necrosome

DOI:  https://doi.org/10.1073/pnas.2507028122
Cell Rep. 2025 Sep 12. pii: S2211-1247(25)01057-5. [Epub ahead of print]44(9): 116286

Pathogenic phosphorylation of linear ubiquitin machinery causes inflammasome sensor degradation.

Yang Yu, Shanshan Yu, Zhe Lu, Lihua Qiang, Yanzhao Zhong, Pupu Ge, Zehui Lei, Changgen Qiu, Yingxu Fang, Xinwen Zhang, Bingxi Li, Yu Pang, Jing Wang, Lingqiang Zhang, Cui Hua Liu, Qiyao Chai.

  Host immune cells are equipped with cytosolic sensors to detect invading pathogens and initiate anti-infectious responses. However, how pathogens undermine host intracellular surveillance for persistent infection is not fully understood. Here, we identify that Mycobacterium tuberculosis protein kinase PknG subverts inflammasome sensor NLRP3-mediated cytokine release and pyroptosis by targeting host linear ubiquitin chain assembly complex (LUBAC). Mechanistically, PknG phosphorylates the LUBAC subunit HOIL-1L to prevent it from engaging in LUBAC formation, thereby suppressing linear ubiquitination of inflammasome adaptor ASC to dampen NLRP3 inflammasome assembly. Meanwhile, this phosphorylation stabilizes and activates HOIL-1L, which, in turn, exerts ubiquitin ligase activity to mediate K48-linked ubiquitination of NLRP3 for degradation. Disrupting the kinase activity or HOIL-1L-interacting region of PknG facilitates host NLRP3-dependent anti-Mtb immunity in mice. Thus, the bacterial kinase disrupts host linear ubiquitin machinery and coopts its ubiquitin ligase subunit to constitute an inter-species enzymatic cascade that drives inflammasome sensor degradation for counteracting immune surveillance.

Keywords:  CP: Molecular biology; Mycobacterium tuberculosis; inflammasome; intracellular immune surveillance; linear ubiquitin chain assembly complex, LUBAC; protein kinase G, PknG; ubiquitination

DOI:  https://doi.org/10.1016/j.celrep.2025.116286
bioRxiv. 2025 Sep 11. pii: 2025.09.10.675376. [Epub ahead of print]

Innate detection of Salmonella replication triggers caspase-8-dependent apoptosis via TLR-driven TNF signaling and NLRC4-mediated sensing of the SPI-2 Type III secretion system.

Beatrice I Herrmann, Maxime Zamba-Campero, Reyna Garcia-Sillas, Winslow W Yost, Lance W Peterson, Justin L Roncaioili, Shelley C Rankin, Dieter M Schifferli, Kodi Ravichandran, Igor E Brodsky.

Salmonella enterica comprises over 2500 serovars that are responsible for over 90 million annual infections and 100,000 deaths worldwide. Despite this diversity, our understanding of innate immune responses to Salmonella is based on extensive study of a few serovars, primarily Typhimurium, including strains that cannot replicate within primary murine macrophages. Non-replicating Salmonella trigger caspase-1 and -11-dependent pyroptosis. Whether the innate immune system distinguishes between replicating and non-replicating intracellular Salmonella is poorly defined. Here we demonstrate that replicating Salmonella enterica induce a distinct pathway of TNF- and caspase-8-driven apoptosis via host TLR4 and Salmonella Pathogenicity Island-2 activity. This pathway is independent of gasdermin D and involves the apoptotic pore protein Pannexin-1. Combined loss of Pannexin-1 and gasdermin D resulted in defective control of systemic Salmonella , indicating that these pathways function together to promote anti- Salmonella host defense. Altogether, our findings uncover a previously unappreciated pathway by which macrophages sense intracellular replicating bacteria.

DOI: https://doi.org/10.1101/2025.09.10.675376
bioRxiv. 2025 Sep 09. pii: 2025.09.04.673995. [Epub ahead of print]

A dominant role of cell death in limiting Chandipura virus propagation at cell-saturating high multiplicity of infection.

Bhawna, Swapnava Basu, Syed Yusuf Mian, Sanchi Arora, Yashika Ratra, Kasturi Ganguly, Sachendra S Bais, Manidipa Banerjee, Abhyudai Singh, Soumen Basak.

Viruses transit from a low to high multiplicity of infection (MOI) regime in infected tissues. Type-1 interferons (IFNs) enforce a cellular state refractory to virus multiplication, while the death of infected cells eliminates viral replicative niche. Here, we investigated how these two innate antiviral mechanisms cooperate at various MOIs upon cell infection by Chandipura virus (CHPV), a cytopathic RNA virus implicated in several outbreaks of acute encephalitis in India. We found that as expected, a gradual increase in the input MOI from 0.02 to 2 led to a proportionate surge in the viral yield. Surprisingly, a further rise to MOI 20 caused a reduction in the progeny titer. Our mathematical modeling together with ex vivo infection studies involving mutant cells suggested that cell death - more so than virus-induced type-1 IFNs - restricted CHPV propagation at cell-saturating high MOIs, leading to a net fall in the yield at MOI 20. We argue that the distinct involvement of innate immune pathways at varied MOIs imparts robust cellular defense against cytopathic viruses.
Significance sentence: Cell death - more so than type-1 interferons - limits Chandipura virus propagation at cell-saturating high multiplicity of infection.
Highlights: # Type-1 IFNs and cell death cooperate at varied MOI in limiting CHPV multiplication.# At sub-saturating low MOI, type-1 IFNs play a dominant role in controlling CHPV propagation.# At cell-saturating high MOI, cell death determines the progeny yield.

DOI: https://doi.org/10.1101/2025.09.04.673995
Nature. 2025 Sep 17.

Myeloperoxidase transforms chromatin into neutrophil extracellular traps.

Garth Lawrence Burn, Tobias Raisch, Sebastian Tacke, Moritz Winkler, Daniel Prumbaum, Stephanie Thee, Niclas Gimber, Stefan Raunser, Arturo Zychlinsky.

Neutrophils, the most abundant and biotoxic immune cells, extrude nuclear DNA into the extracellular space to maintain homeostasis. Termed neutrophil extracellular traps (NETs), these protein-modified and decondensed extracellular DNA scaffolds control infection and are involved in coagulation, autoimmunity and cancer1,2. Here we show how myeloperoxidase (MPO), a highly expressed neutrophil protein, disassembles nucleosomes, thereby facilitating NET formation, yet also binds stably to NETs extracellularly. We describe how the oligomeric status of MPO governs both outcomes. MPO dimers interact with nucleosomal DNA using one protomer and concurrently dock into the nucleosome acidic patch with the other protomer. As a consequence, dimeric MPO displaces DNA from the core complex, culminating in nucleosome disassembly. On the other hand, MPO monomers stably interact with the nucleosome acidic patch without making concomitant DNA contacts, explaining how monomeric MPO binds to and licences NETs to confer hypohalous acid production in the extracellular space3. Our data demonstrate that the binding of MPO to chromatin is governed by specific molecular interactions that transform chromatin into a non-replicative, non-encoding state that offers new biological functions in a cell-free manner. We propose that MPO is, to our knowledge, the first member of a class of proteins that convert chromatin into an immune effector.

DOI: https://doi.org/10.1038/s41586-025-09523-9