bims-cediti 2026-06-07 papers

bims-cediti

Biomed News

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

Issue of 2026–06–07
nine papers selected by
Kateryna Shkarina, Universität Bonn

LASER couples damage sensing to ESCRT assembly for lysosome repair.
Licensed to pore: Gasdermins in action.
HSD17B11 maintains FSP1 localization on lipid droplets to support ferroptosis defense.
Nociceptive neurons inhibit neutrophil extracellular trap formation via MLKL-licensed histone release.
TRIM21 induces selective autophagy of viruses and bacteria.
Dual lineages of Langerhans cells cooperate to restore the immune barrier after skin injury.
Spermine is an endogenous iron chelator that inhibits ferroptosis.
NETosis associates with human TB lung tissue destruction and disease pathogenesis.
Airway mucins function as endogenous inhibitors of neutrophil extracellular traps.

Nature. 2026 Jun 03.

LASER couples damage sensing to ESCRT assembly for lysosome repair.

Claire S Goul, Aakriti Jain, Samira Yitiz, Zahra E Soltani, Serim Yang, Simon Rapp, Martina Spacci, Scot Federman, James Sacco, Huinan Li, Lauren D Enriquez, Nalan Liv, Laralynne Przybyla, Roberto Zoncu.

Lysosomal membrane integrity is essential for cell survival, but how damage sensing is spatiotemporally coupled to repair remains poorly understood. Recruitment and assembly of endosomal sorting complex required for transport (ESCRT) I-III rapidly counteracts membrane damage, but it is unclear how ESCRT-I recognizes defective lysosomal membranes. Here, leveraging genome-wide CRISPRi screens in a damage-sensitized genetic background, we identified LC3/GABARAP-assisted stimulator for ESCRT recruitment (LASER), a multicomponent protein assembly that forms rapidly upon calcium release from damaged lysosomes and couples sensing of lysosomal membrane damage to ESCRT-dependent repair. At the core of LASER is TFG, an endoplasmic reticulum exit-site-resident protein that translocates to damaged lysosomes by binding to ATG8 family proteins (LC3 and GABARAP) conjugated to lysosomal phospholipids. ATG8-bound TFG forms oligomeric assemblies that directly recruit the essential ESCRT-I subunit TSG101 via conserved motif recognition enhanced by avidity-driven interactions. TFG binding to TSG101 stimulates sequential ESCRT-I-II-III polymerization and promotes membrane repair. TFG mutations that drive hereditary spastic paraplegia disrupt its oligomerization and impair lysosomal ESCRT recruitment and membrane resealing, implicating defective repair as a driver of TFG-associated neurodegeneration. Thus, LASER promotes ESCRT polymerization at damaged lysosomes and couples damage sensing to membrane repair.

DOI: https://doi.org/10.1038/s41586-026-10604-6
Cell Chem Biol. 2026 Jun 01. pii: S2451-9456(26)00153-4. [Epub ahead of print]

Licensed to pore: Gasdermins in action.

Natália Ketelut-Carneiro, Anukriti Mathur, Katherine A Fitzgerald.

  Gasdermins (GSDMs) are a conserved family of pore-forming proteins that execute pyroptosis. Proteolytic activation of GSDMs by caspases, granzymes, or microbial enzymes liberates the N-terminal domain, which oligomerizes and inserts into membranes to form pores, releasing interleukin-1 cytokines, alarmins, and cytosolic contents. Recent structural and biochemical studies have provided mechanistic insight into GSDM cleavage, lipid recognition, and post-translational modifications, which regulate pore formation and pyroptosis. GSDMs sit at the nexus of host defense and pathology, simultaneously constraining pathogens while amplifying tissue injury, septic shock, and chronic inflammation. In sterile contexts, GSDMs contribute to autoimmunity and barrier injury while paradoxically supporting tissue regeneration. Their roles in cancer are highly context-dependent, spanning across tumor suppression, immune activation, and immune evasion. Emerging therapeutic strategies, including small-molecule inhibitors and agonists, underscore the translational potential of targeting GSDMs. This review integrates mechanistic, physiological, and translational advances defining GSDMs as versatile regulators of immunity and disease.

Keywords:  Gasdermin; infectious diseases and cancer; inflammation; programmed cell death

DOI:  https://doi.org/10.1016/j.chembiol.2026.05.001
bioRxiv. 2026 May 21. pii: 2026.05.19.726342. [Epub ahead of print]

HSD17B11 maintains FSP1 localization on lipid droplets to support ferroptosis defense.

Valeria Montenegro Vazquez, Baley A Goodson, Oralia M Kolaczkowski, Halima Akter, Li Chen, Nikesh Narang, Jaya Rajaiya, Monica Rosas Lemus, Jing Pu.

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation, and lipid droplets (LDs) are increasingly recognized as important regulators of this process. Consistent with this role, the anti-ferroptotic factor ferroptosis suppressor protein 1 (FSP1) is known localizing on LDs through N-myristoylation-dependent membrane targeting, where it protects LD lipids from peroxidation. Here, we identify the LD protein HSD17B11 as an additional factor required for maintaining both FSP1 localization on LDs and cellular FSP1 abundance. Silver staining followed by mass spectrometry analysis of purified LD proteins identified reduced LD-associated FSP1 in HSD17B11-deficient cells, which was further validated by immunoblotting and imaging analyses. Mechanistically, HSD17B11 physically interacted with FSP1 and was required to preserve FSP1 association with LDs. Mutational analyses further demonstrated that both FSP1 N-myristoylation and an intact HSD17B11 interaction interface are necessary for LD targeting. Correspondingly, HSD17B11 deficiency reduced LD-associated and total cellular FSP1 levels and increased cellular sensitivity to lipid oxidative stress. Together, our findings identify HSD17B11 as a previously unrecognized regulator of LD-associated FSP1 and reveal an additional mechanism controlling compartmentalized ferroptosis defense.

DOI: https://doi.org/10.64898/2026.05.19.726342
Cell Rep. 2026 Jun 01. pii: S2211-1247(26)00535-8. [Epub ahead of print]45(6): 117457

Nociceptive neurons inhibit neutrophil extracellular trap formation via MLKL-licensed histone release.

Han Meng, Wenchao Hu, Enming Kang, Qing Xu, Pengfei Wang, Xuyang Yi, Honghui Mao, Bowen Zhang, Xinyu Meng, Yanjin Wang, Yanchen Tan, Zhuqing Mao, Xingxing Zheng, Lina Niu, Ming Shi, Ceng Luo, Shengxi Wu, Rougang Xie, Yazhou Wang.

  Neutrophil-involved neuroinflammation in dorsal root ganglion (DRG) plays double-sword roles in chronic pain. How DRG neuron-neutrophil interaction contributes to chronic pain remains unclear. Here, we report that MLKL, a key molecule in necroptosis, is constitutively expressed in the nucleus of nociceptive neurons and binds to histone H3. Periphery inflammation disrupted MLKL/H3 interaction, leading to cytoplasmic translocation of MLKL and release of histone H3. Extracellular histone H3 induces neuronal hyperactivity, neutrophil extracellular trap (NET), and hyperalgesia, possibly through P2X7 receptor and Toll-like receptor 4. Nociceptive-specific depletion of Mlkl significantly decreased pain threshold and exacerbated NET formation independent of cell death. Neutralizing extracellular histone, clearing extracellular DNA or restoring nuclear localization of MLKL can reduce both NET formation and hyperalgesia in Mlkl-/-mice. These data demonstrated that the nociceptive neuron-neutrophil interaction mediated by this MLKL-histone-NET cascade may serve as a potential therapeutic target for chronic inflammatory pain.

Keywords:  CP: neuroscience; MLKL; histone; inflammatory pain; neutrophil extracellular trap

DOI:  https://doi.org/10.1016/j.celrep.2026.117457
Mol Cell. 2026 Jun 04. pii: S1097-2765(26)00285-6. [Epub ahead of print]

TRIM21 induces selective autophagy of viruses and bacteria.

Tyler Rhinesmith, Anna Albecka, Marina Vaysburd, Claudia Puri, Jakub Luptak, Jerome Boulanger, Quynh-Mai Nguyen Le, Matthew J Gratian, Kevin O'Connell, Lara Few, Mark Donaldson-Wing, Patrycja Kozik, David C Rubinsztein, Leo C James.

  TRIM21 is an exceptionally versatile ubiquitin ligase that can be directed by antibodies to target oligomeric protein scaffolds, viral capsids, and proteopathic aggregates for intracellular degradation. How the cell degrades these typically resistant substrates remains poorly understood. To address this, we used TRIM21 viral restriction to create a genome-wide phenotypic screen for antibody-dependent capsid degradation. We identify an antimicrobial selective macroautophagy pathway in mammalian cells, which we term "antibody-directed xenophagy" (ADX). We show that this mechanism restricts structurally diverse pathogens, including adenovirus and Salmonella. Using quantitative microscopy, we demonstrate that TRIM21 rapidly intercepts antibody-pathogen complexes, leading to ubiquitin ligase activation. Following this, selective autophagy adaptors are recruited, and viral cargoes are delivered to lysosomes. This process reduces Salmonella pathology and bacterial tissue invasion in mice. We propose that TRIM21 evolved through competition with pathogens to induce autophagy of diverse and complex substrates, potentially explaining its versatility for targeted protein degradation.

Keywords:  antibody; antimicrobial response; antiviral immunity; autophagy; innate immunity; protein degradation; targeted protein degradation; ubiquitin ligase; ubiquitin proteasome system; xenophagy

DOI:  https://doi.org/10.1016/j.molcel.2026.04.031
bioRxiv. 2026 May 28. pii: 2026.05.25.727646. [Epub ahead of print]

Dual lineages of Langerhans cells cooperate to restore the immune barrier after skin injury.

Axel D Schmitter-Sánchez, Nicholas Basista, Artem Kiselev, Sudhanshu Mishra, Hyeri Kim, Audrey Bench, Catherine Matte-Martone, Min-Soo Seo, Gun Woo Lee, Sangbum Park.

Langerhans cells (LCs) are key immune sentinels of the epidermis. How this network reorganizes to safeguard epidermal immunity after injury has remained unclear. Here, we uncover a previously unrecognized two-lineage program of LC repopulation during wound repair. Classically, tissue-resident embryonically derived LCs (eLCs) migrate to lymph nodes in response to antigens. In contrast, we find that injury triggers nearby eLCs to migrate into wounds, providing immediate coverage. In parallel, circulating monocytes infiltrate the skin and differentiate into long-lived monocyte-derived LCs (mLCs) that integrate stably into the network. We identify the chemokine receptor CXCR2 as a novel regulator of eLC migration into wounds, distinct from the CXCR4/CCR7 pathways mediating LC egress to lymph nodes. Pharmacological inhibition of CXCR2 impairs directional eLC migration and is accompanied by increased mLC infiltration, preserving immune barrier density. These findings reveal a coordinated and flexible two-lineage repair program that ensures robust restoration of epidermal immunity.

DOI: https://doi.org/10.64898/2026.05.25.727646
Nature. 2026 Jun 03.

Spermine is an endogenous iron chelator that inhibits ferroptosis.

Man Li, Xuexin Yu, Shuqin Ouyang, Xiaohong Chen, Huiqi Yu, Yuanji Liu, Ziwen Li, Chunhua Yu, Rui Kang, Christine Gaillet, Ludovic Colombeau, Raphaël Rodriguez, Libing Song, Guido Kroemer, Daolin Tang, Jun Li.

Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation1. Here we identify spermine-a polyamine derived from spermidine2-as an endogenous iron chelator that directly suppresses ferroptosis. Integrating metabolomics, stable isotope tracing and biophysical studies of the interaction between spermine and Fe2+ ions, we demonstrate that aldehyde dehydrogenase 18 family member A1 (ALDH18A1) promotes an alternative glutamine-dependent pathway for de novo spermine synthesis. This process limits iron availability and lipid peroxidation in hepatocellular carcinoma. Genetic or pharmacological inhibition of ALDH18A1-through knockout, short hairpin RNA delivered using adeno-associated virus (AAV), or the small molecule inhibitor YG1702-triggers ferroptosis and impairs both spontaneous and chemically induced hepatocarcinogenesis. Conversely, supplementation of spermine protects against ferroptosis-associated ischaemia-reperfusion injury across multiple tissues, including the liver, intestine and kidneys. These findings uncover a pathophysiologically relevant metabolic circuit in which spermine-mediated iron chelation suppresses ferroptosis.

DOI: https://doi.org/10.1038/s41586-026-10597-2
EMBO Mol Med. 2026 Jun 02.

NETosis associates with human TB lung tissue destruction and disease pathogenesis.

Kimone L Fisher, Thabo Mpotje, Kievershen Nargan, Denelle Moodley, Kerishka Rajkumar-Bhugeloo, Omolara O Baiyegunhi, Threnesan Naidoo, Rajhmun Madansein, Mike Sathekge, Alasdair Leslie, Gillian Tomlinson, Gabriele Pollara, Mahdad Noursadeghi, Adrie J C Steyn, Thumbi Ndung'u, Mohlopheni J Marakalala.

Understanding drivers of tuberculosis (TB) associated lung pathological damage is vital in identifying targets for host directed therapies (HDT). NETosis is a neutrophil specific cell death characterized by release of neutrophil extracellular traps (NETs). The role of NETosis in TB-associated lung damage and disease pathogenesis is still poorly understood. We analysed human lung TB granuloma samples using a proteomics approach, which revealed enrichment of neutrophil-associated proteins in necrotic regions of caseous and cavitary granulomas. Using immunohistochemistry (IHC), we validated the abundance of neutrophil-associated proteins, including myeloperoxidase (MPO), cytochrome b-245 beta chain (CYBB) and neutrophil cytosolic factor 1(NCF1), as well as NETosis markers, neutrophil elastase (NE) and citrullinated H3, in necrotizing caseum of human TB granulomas. MPO protein expression was also more abundant in the plasma of TB patients compared to healthy and latently infected (LTBI) participants. MPO directly correlated with an inflammatory disease marker, IP-10. In addition, MPO and IP-10 colocalized in caseous lesions. In-vitro drug inhibition assays were used to investigate potential drivers of NETosis, with pharmaceutical inhibition of MPO, NE and CYBB resulting in reduction of NETosis induced by Mycobacterium tuberculosis (Mtb). Using RT-qPCR we analysed the expression of 18 neutrophil associated genes in the blood of healthy (n = 20), latent TB infection (LTBI) (n = 20) and TB (n = 30) participants. We found that MPO, NCF1 and NCF2 were upregulated in the TB group. Furthermore, the NETosis-associated genes were induced in a human standardized antigen challenge model. Our data shows evidence of NETosis as an associate of lung pathological damage in TB and identifies key drivers of the neutrophil cell death that can be intercepted as potential HDT targets to reduce neutrophil driven lung pathological damage.

DOI: https://doi.org/10.1038/s44321-026-00435-3
bioRxiv. 2026 May 18. pii: 2026.05.14.719291. [Epub ahead of print]

Airway mucins function as endogenous inhibitors of neutrophil extracellular traps.

Allison Boboltz, Vaidehi Rathi, Gregg A Duncan.

Neutrophils recruited to the airways are important for innate lung defense and can release neutrophil extracellular traps (NETs) to capture and eliminate microbes. While NETs are not abundant in healthy airways, uncontrolled NETosis is a known pathological feature and contributor to both chronic and acute respiratory diseases. Prior studies have shown that mucin glycoproteins secreted in the oral cavity and cervicovaginal tract can modulate NETosis, but it remains unknown whether mucins secreted in the respiratory tract influence NET formation. In these studies, we discovered that human airway mucus strongly inhibits NETosis in primary human neutrophils in a sialic acid dependent manner. In comparison, mucus produced by human airway epithelial cells genetically engineered to lack either MUC5B or MUC5AC secreted airway mucins showed a reduced ability to suppress NETosis. To assess how the lung microenvironment in obstructive lung diseases may influence mucus-dependent NET formation, we engineered a synthetic, mucin-laden hydrogel model with physical properties resembling that of mucus in a healthy lung and a disease-affected lung. When neutrophils were cultured on these gel substrates, we found that increasing gel stiffness led to a significantly greater extent of NETosis. Together these data demonstrate a new functional role of airway mucus in modulating neutrophil homeostasis in the respiratory tract and provide evidence that mucus dysfunction in disease can impair its ability to regulate NETosis.

DOI: https://doi.org/10.64898/2026.05.14.719291