bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–03–01
sixteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. Telomeric repeat-containing RNA G-quadruplexes trigger ZBP1-mediated cell death.
  2. The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.
  3. Antiviral Inflammasomes and How to Find Them.
  4. Dickkopf1 is a novel endogenous ligand for priming NLRP3 inflammasome in macrophages via TLR4.
  5. Terminal Loop Sequences in Viral Double-Stranded RNAs Modulate RIG-I Signaling.
  6. Nerve Injury-Induced Protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.
  7. Skin androgens regulate Staphylococcus aureus pathogenicity via quorum sensing.
  8. Pyroptosis: Turning Up the Heat on Cancer.
  9. Proximity labeling of the Listeria monocytogenes surface reveals pathogen control of a host deubiquitinase.
  10. Homotypic SLAMF1:SLAMF1 interactions between innate T cells and neutrophils activate fungal killing by neutrophils.
  11. Solution NMR reveals micelle-stabilized α-helical segments flanking the RIPK1 RHIM amyloid core.
  12. Inflammasome adaptor ASC promotes sustained neuroinflammation and mild cognitive impairment in a closed-head injury model.
  13. Modulation of immune cells and metabolic reprogramming in efferocytosis.
  14. Listeria-infected macrophages promote biomechanical alterations in endothelial cell monolayers for transmigration.
  15. A gated hydrophobic funnel within BAX binds bioactive lipids to potentiate pro-apoptotic function.
  16. Hyperglycemia promotes maladaptive Dectin-1 signaling and impairs skin antifungal host defense.
  1. Nat Commun. 2026 Feb 23.
    Telomeric repeat-containing RNA G-quadruplexes trigger ZBP1-mediated cell death.
    Geng Qin, Chuanqi Zhao, Chengming Gao, Wenxuan Hu, Na Zhang, Jinsong Ren, Xiaogang Qu.
      Z-DNA-binding protein 1 (ZBP1) is a nucleic acid sensor with two Z-DNA-binding domains (Zα domains) that bind Z-DNA and Z-RNA, mediating inflammatory cell death in development and disease. A recent study has demonstrated that the truncated isoform ZBP1-S senses telomeric repeat-containing RNA (TERRA), activating innate immune signaling and triggering cell death. However, the precise mechanism on how ZBP1-S senses TERRA remains unknown. G-quadruplexes (G4s) are non-canonical secondary structures of nucleic acids that can form within guanine (G)-rich strands of DNA or RNA, including TERRA. Here, we demonstrate that ZBP1-S directly senses G4 structures within TERRA, leading to ZBP1-S oligomerization and subsequent induction of inflammatory cell death. Furthermore, G4-specific binding ligands can compete with ZBP1-S for binding to TERRA G4s and inhibit ZBP1-S mediated activation of interferon signaling. Therefore, this work deciphers a hitherto uncharacterized mechanism that links TERRA G4s with ZBP1-S activity in triggering inflammatory cell death.
    DOI:  https://doi.org/10.1038/s41467-026-69989-7
  2. Mol Cell. 2026 Feb 24. pii: S1097-2765(26)00071-7. [Epub ahead of print]
    The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.
    Dominic A Ritacco, Hamna Shahnawaz, Antonia Oduguwa, Jacob Hawk, Brianna Vizcaino, Donna L Farber, Ryan G Gaudet.
      Lysosomal damage is an endogenous danger signal, but its significance for innate immunity and the specific signaling pathways it engages remain unclear. Here, we uncover an immune-inducible pathway that connects lysosomal damage to mitochondrial DNA (mtDNA) efflux and type I IFN production. We find that transient lysosomal damage elicits sub-lethal mitochondrial outer membrane permeabilization (MOMP) via BAK/BAX macropores; however, the inner mitochondrial membrane (IMM) maintains a barrier against wholesale mtDNA release. Priming with type II IFN (IFN-γ) induced the antibacterial factor APOL3, which, upon sensing lysosomal damage, targets mitochondria undergoing MOMP to selectively permeabilize the IMM, enhance mtDNA release, and potentiate downstream cGAS signaling. Biochemical and cellular reconstitution revealed that, analogous to its bactericidal detergent-like mechanism, APOL3 permeabilized the IMM by solubilizing cardiolipin. Our findings illustrate how cells enlist an antibacterial protein to expedite the breakdown of endosymbiosis and facilitate a heightened response to injury and infection.
    Keywords:  DNA; damage; innate immunity; interferon; intracellular bacteria; lysosome; mitochondrion; viruses
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.029
  3. Viruses. 2026 Jan 28. pii: 173. [Epub ahead of print]18(2):
    Antiviral Inflammasomes and How to Find Them.
    Jennifer Deborah Wuerth, Florian Ingo Schmidt.
      Inflammasomes are signaling complexes of the innate immune system that are assembled in distinct sentinel cell types to coordinate inflammation. As demonstrated by the emergence of viral antagonists and evasion mechanisms, inflammasomes are critical to contain viral infections. As virions are entirely composed of host cell-derived molecules, infection is either recognized by molecules or modifications exposed in unusual compartments, or by activities and host cell damage indicative of virus replication. Rather than enumerating all viruses that activate inflammasomes, this review classifies common pathways or signatures that activate antiviral inflammasomes. We define a set of minimal criteria that we think is critical to prove virus-triggered inflammasome assembly. We further discuss the consequences of virus-induced inflammasome assembly and define relevant open questions in the field.
    Keywords:  ASC speck; inflammasome; inflammation; innate immune system; retrovirus; virus
    DOI:  https://doi.org/10.3390/v18020173
  4. J Immunol. 2026 Feb 09. pii: vkaf367. [Epub ahead of print]215(2):
    Dickkopf1 is a novel endogenous ligand for priming NLRP3 inflammasome in macrophages via TLR4.
    Theingi Aung, SuJeong Song, Joyce Kasongo, Hisashi Harada, Shijun Zhang, Octavian Henegariu, Wook-Jin Chae.
      Dickkopf1 (DKK1) is a quintessential Wnt antagonist and immunomodulator in various inflammatory diseases. The underlying molecular mechanisms of DKK1-mediated immunomodulation remain elusive. Here, we identified TLR4 as a new receptor for DKK1, activating NFκB-mediated gene expression. Subsequently, this event resulted in pyroptosis via the NLRP3 inflammasome in human and mouse macrophages. DKK1 employed TLR4 to initiate the NFκB signaling cascade via MyD88. Activation of the MyD88-TAK1-NFκΒ pathway by DKK1 increased the expression of HIF1α, NFκB, and NLRP3 proteins. Unlike LPS, DKK1 did not induce IRAK4 phosphorylation, while the interaction between MyD88 and IRAK4 was maintained for downstream signaling activation. DKK1 did not induce IRF3 phosphorylation in the nucleus and failed to induce IFNB gene expression, indicating that LPS signaling is differentially regulated. DKK1 primed macrophages via TLR4-MyD88, resulting in NFκB pathway activation that mediates NLRP3 inflammasome-mediated pyroptosis via caspase-1 and gasdermin D maturation with various NLRP3 inflammasome activators, including nigericin. Our results demonstrated that DKK1 is a novel endogenous priming ligand that differentially augments the NFκB pathway activation via TLR4 and primes mouse and human macrophages for NLRP3 inflammasome activation.
    Keywords:  Dickkopf1; TLR4; inflammasome; macrophage
    DOI:  https://doi.org/10.1093/jimmun/vkaf367
  5. RNA. 2026 Feb 23. pii: rna.080913.125. [Epub ahead of print]
    Terminal Loop Sequences in Viral Double-Stranded RNAs Modulate RIG-I Signaling.
    Matthew Hackbart, Patrick Wang, Victoria Gnazzo, Carolina B Lopez.
      Detection of foreign RNAs is a crucial activation step for innate immunity pathways in response to viral infections. Retinoic acid-inducible gene I (RIG-I) is a cytoplasmic RNA sensor that triggers type I and III interferon (IFN) expression and activates the antiviral response in response to RNA virus infection. The activating ligand for RIG-I has been shown to be 5'-triphosphated, blunt-ended, double-stranded (ds)RNA, but questions remain on the impact of other RNA motifs on RIG-I activation. Here we show that immune-activating copy-back viral genomes (cbVGs) contain RNA stem loops away from the 5' end of the RNA that enhance RIG-I signaling and IFN expression. Importantly, the sequence of the terminal loops of the activating motifs impacts the strength of IFN expression. Additionally, we show that synthetic versions of these cbVG-derived stem loops trigger innate immune responses in mice demonstrating their potential as immunostimulants in vivo.
    DOI:  https://doi.org/10.1261/rna.080913.125
  6. bioRxiv. 2026 Feb 11. pii: 2026.02.09.704867. [Epub ahead of print]
    Nerve Injury-Induced Protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.
    Jin Zhang, Miranda Bustamante, Yang Shi, Ken-Ichi Nakajima, Xinbin Chen.
      Nerve injury-induced protein 1 (NINJ1), a cell adhesion molecule, is oligomerized during lytic cell death and mediates plasma membrane rupture to release large intracellular molecules that propagate the inflammatory response. We and others previously showed that NINJ2, a close relative of NINJ1, does not promote plasma membrane rupture to spread inflammation. Here, we identify that NINJ2 is necessary for the lysosome membrane integrity to protect cells from ferroptosis. Specifically, we found that NINJ2 localizes to lysosomes and interacts with LAMP1, an anchor glycoprotein of the lysosome membranes and a sensor of stressed lysosomes. We also found that loss of NINJ2 exacerbates lysosomal membrane permeabilization (LMP), which allows for selective leakage of lysosomal contents, such as labile iron, into the cytosol. Accordingly, loss of NINJ2 elevates cellular labile iron accumulation and decreases expression of ferritins, the primary intracellular iron storage protein complexes. Mechanistically, we found that loss of NINJ2 promotes ferritin FTH degradation in lysosomes, which can be reversed by knockdown of LAMP1. Moreover, we found that loss of NINJ2 sensitizes cells to ferroptosis induced by RSL3 and Erastin, consistent with a recent study that loss of Ninj2 predisposes mice to chronic inflammation. Together, these findings uncover a previously unrecognized activity of NINJ2 from lysosome homeostasis to ferroptosis, which can be explored as a cancer therapeutic strategy especially considering that NINJ2 and ferritins are found to be overexpressed and positively associated with iron-addicted cancers.
    DOI:  https://doi.org/10.64898/2026.02.09.704867
  7. Nat Microbiol. 2026 Feb 27.
    Skin androgens regulate Staphylococcus aureus pathogenicity via quorum sensing.
    Maria Sindhura John, Mahendran Chinnappan, Camille I Sturges, Methinee Artami, Mohini Bhattacharya, Rebecca A Keogh, Jeffrey S Kavanaugh, Shivani Jain, Hanna Gedamu, Jessica Komarovsky, Mauricio Velasquez, Tripti Sharma, Jeffrey G McDonald, Alexander R Horswill, Tamia A Harris-Tryon.
      Skin cells secrete testosterone, with greater amounts secreted at the skin surface of males compared with females. Males are also more susceptible to skin infections than females. Here we report that mice engineered with testosterone-deficient skin are resistant to methicillin-resistant Staphylococcus aureus infections. Testosterone promoted the expression of S. aureus cytotoxic virulence factors by activating the accessory gene regulator (agr) quorum-sensing pathway in a concentration-dependent manner and independent of quorum-sensing-activating auto-inducing peptides. Mutational analysis revealed that a functional histidine kinase AgrC in S. aureus was required for testosterone to exert its effect, with in silico evidence indicating a direct interaction between testosterone and AgrC. An isomer of testosterone, enantiomer-testosterone, that blocked bacterial quorum sensing, inhibited S. aureus-induced cytotoxicity of human cells. These findings advance our understanding of how the skin regulates bacterial virulence and reveals a potential therapeutic strategy for the management of infections.
    DOI:  https://doi.org/10.1038/s41564-026-02261-2
  8. Annu Rev Immunol. 2026 Feb 24.
    Pyroptosis: Turning Up the Heat on Cancer.
    Zhibin Zhang, Judy Lieberman.
      The major effector cells of antitumor immunity are killer lymphocytes that recognize and eliminate tumor cells. The fact that tumor cells look a lot like normal cells poses a challenge to antitumor immune control. A danger signal from the tumor or from antigen-presenting cells that have taken up dying tumor cells is needed to distinguish tumor cells from normal cells to fully activate killer cell effector functionality and memory and thereby control the tumor. How a tumor cell dies strongly affects whether the immune system sees it as dangerous. Activation of innate immunity in the tumor, including interferon signaling and necrotic cell death (e.g., necroptosis and pyroptosis), sounds a potent immune alarm. Pyroptosis plays an important role in tumor immunity by generating an inflamed tumor microenvironment. However, it is a double-edged sword that can both promote tumorigenesis and increase the effectiveness and cytotoxicity of cancer therapy. In this article, we review what is known about the role of tumor cell pyroptosis, which is arguably the most inflammatory type of cell death, in antitumor immunity and discuss whether it could be safely harnessed to broaden the range of tumors that respond to immunotherapy.
    DOI:  https://doi.org/10.1146/annurev-immunol-082423-041848
  9. bioRxiv. 2026 Feb 18. pii: 2026.02.17.706400. [Epub ahead of print]
    Proximity labeling of the Listeria monocytogenes surface reveals pathogen control of a host deubiquitinase.
    Patrick J Woida, Maisie W Smith, Rebecca L Lamason.
      Intracellular pathogens must navigate the crowded cellular environment to establish infection. Listeria monocytogenes achieves this by recruiting host factors to its surface to hijack the host actin cytoskeleton for motility, form membrane protrusions, and spread from cell to cell. Although these types of Listeria -host interactions are critical for infection, systematic characterization of this interface has been limited. Here, we implement surface display of the promiscuous biotin ligase split-TurboID to profile host proteins recruited to the surface of L. monocytogenes during intracellular infection. This approach identified the host deubiquitinase CYLD as a protein selectively enriched at the pathogen surface. While CYLD promotes infection by suppressing autophagy and innate immunity in macrophages, how L. monocytogenes recruits and appropriates CYLD function in other cell types has remained unclear. We demonstrate that the E3 ligase RNF213 decorates bacterial poles with M1-linked linear ubiquitin, thereby redirecting CYLD to the bacterial surface. We further show ubiquitin is not sufficient to recruit CYLD but requires the L. monocytogenes secreted effector internalin C (InlC). Despite its presence at the bacterial surface, CYLD does not deubiquitinate bacteria or regulate autophagic bacterial clearance in infected epithelial cells. Instead, CYLD and InlC protect L. monocytogenes from IFN-γ- and RNF213-dependent restriction of cell-to-cell spread. Overall, our work profiling the bacterial surface-host interactome has identified a new mechanism by which InlC spatially reprograms CYLD activity, uncoupling its canonical immune functions to promote cell-to-cell spread in epithelial cells. These findings highlight how L. monocytogenes exploits, a host deubiquitinase, to perform cell-type-specific functions during infection.
    DOI:  https://doi.org/10.64898/2026.02.17.706400
  10. bioRxiv. 2026 Feb 20. pii: 2026.02.19.706741. [Epub ahead of print]
    Homotypic SLAMF1:SLAMF1 interactions between innate T cells and neutrophils activate fungal killing by neutrophils.
    Lindsay S Lau, Sarah Lichtenberger, Cleison Ledesma Taira, Bruce S Klein, Marcel Wüthrich.
      Neutrophils and monocytes are the main fungal effector cells in restricting Blastomyces dermatitidis ( Bd) and other fungi at the respiratory mucosa. However, understanding how phagocytes become activated and recruited to the site of infection is still incompletely understood. Innate lymphocytes and myeloid cells have been found to communicate and play an essential part in activating neutrophils and other effector cells to kill fungi. Here, we identified that Signaling Lymphocytic Activation Molecule 1 (SLAMF1) is a key host immune receptor involved in orchestrating a cellular and molecular signaling network that leads to the activation of phagocytes. By using mice to conditionally eliminate SLAMF1 receptor expression on innate CD4 + or TCRγδ + T cells, we uncovered that these innate lymphocytes augment neutrophil killing of Bd in a SLAMF1 dependent manner. SLAMF1 expression on neutrophils enabled homotypic SLAMF1:SLAMF1 interactions with innate CD4 + T cells, which prompted release of soluble factors that activated neutrophils to kill fungi. Our work furnishes new mechanistic insight about the role of SLAMF1 in mobilizing innate immune cells to induce phagocyte-driven killing of inhaled fungi.
    Author Summary: Emerging fungal diseases represent a significant and growing global public health threat fueled by increased anti-fungal resistance and rising number of immunocompromised individuals. Most fungal infections are respiratory and occur when inhaled fungal spores settle in the lungs and cause inflammation or tissue damage. The innate immune system is the first line of defense in the lungs but the mechanisms by which the host immune system becomes activated and mounts a protective response is still not completely understood. We identified a receptor on innate immune cells that facilitates communication between cells and recruits and activates killer cells that engulf and destroy the fungal pathogen. We uncovered that the receptor on the cell surface of innate immune cells mediates its function through cell contact and induction of soluble factors. Our work offers new mechanistic insight about how the innate immune system becomes activated by the presence of fungi and orchestrates an effective host response. We envision that soluble receptor could be harnessed for future anti-fungal therapy.
    DOI:  https://doi.org/10.64898/2026.02.19.706741
  11. Biochem Biophys Res Commun. 2026 Feb 21. pii: S0006-291X(26)00277-9. [Epub ahead of print]809 153513
    Solution NMR reveals micelle-stabilized α-helical segments flanking the RIPK1 RHIM amyloid core.
    Paula Polonio, Gustavo A Titaux-Delgado, Miguel Mompeán.
      Receptor Interacting Protein Kinase 1 (RIP1 or RIPK1) can transition from a monomeric state to amyloid assemblies during cell signaling via a conserved RIP homotypic interaction motif (RHIM). Through RHIM-RHIM interactions, RIPK1 forms both homomeric and heteromeric amyloids implicated in programmed cell death, but solution-state characterization of unassembled RIPK1 is hindered by rapid aggregation. Building on our recent RIPK1 fibril structure, we designed an aggregation-slowing mutant (N545D) and show that two segments within RIPK1's disordered domain display nascent helical propensity under near-physiological pH conditions. SDS micelles further stabilize these helices and enable measurements on the wild-type sequence. Notably, analogous conditions do not reveal comparable α-helical populations in RIPK3, despite a conserved RHIM sequence and amyloid structure endpoint.
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153513
  12. J Clin Invest. 2026 Feb 24. pii: e199818. [Epub ahead of print]
    Inflammasome adaptor ASC promotes sustained neuroinflammation and mild cognitive impairment in a closed-head injury model.
    Tao Li, Sergio Castro-Gomez, Pablo Botella Lucena, Ana Vieira-Saecker, Stephanie Schwartz, Yingying Ding, Yushuang Deng, Maling Guo, Valentin Stein, Douglas T Golenbock, Eicke Latz, Michael T Heneka.
      Mild traumatic brain injury (mTBI) from closed-head injuries (CHI) can lead to prevalent neuropsychiatric disorders, including mood disorders and an increased risk for neurodegenerative diseases and dementia. Inflammasomes are molecular complexes crucial for neuroinflammation and secondary damage after trauma, however their role in mild CHI is poorly understood. In this study, we investigate the cellular expression of inflammasome-related genes and their functional significance in CHI models. Single-cell RNA sequencing analysis of cortical tissue after trauma revealed selective expression of Asc (also known as Pycard), which encodes the inflammasome adaptor Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC), predominantly in microglial clusters. Sustained upregulation of inflammasome-related proteins, microglia activation and astrocyte reactivity persisted up to 21 days in a model for mTBI, with this pattern significantly reduced in Asc-/- mice. Importantly, mild cognitive impairment induced after mild CHI was largely abrogated in Asc-/- mice. These findings suggest that ASC, as the primary inflammasome adaptor, plays a critical role in sustaining neuroinflammation and contributes to cognitive deficits after mild CHI. This study provides insights into the molecular neuroinflammatory mechanisms underlying CHI, potentially informing future therapeutic strategies.
    Keywords:  Dementia; Inflammation; Innate immunity; Neuroscience; Transcriptomics
    DOI:  https://doi.org/10.1172/JCI199818
  13. Cell Death Dis. 2026 Feb 25.
    Modulation of immune cells and metabolic reprogramming in efferocytosis.
    Karen Cristina Oliveira, Caroline Maria Marcos, Letícia de Aquino Penteado, Naiara Naiana Dejani, Pedro M Moraes-Vieira, Alexandra I Medeiros.
      Under physiological conditions, cell apoptosis is a silent death process during tissue renewal and remodeling. The phagocytosis of apoptotic cells, known as efferocytosis, is a key process performed primarily by macrophages and dendritic cells, as well as by non-professional phagocytes, such as epithelial cells and fibroblasts. This process, which involves the removal of apoptotic cells, is not just a routine task. It plays a significant role in producing anti-inflammatory mediators that are instrumental in maintaining tissue homeostasis. However, during infection, pathogens can induce different patterns of cell death, including apoptosis. Efferocytosis of infected apoptotic cells is a crucial part of the host defense mechanism. It aids in bacterial clearance, activates the effector functions of phagocytes, and directs the activation of CD4+T lymphocytes. The different stages of the efferocytosis process are not just a sequence of events, but a complex interplay that can interfere with the microenvironment by releasing soluble mediators ("find-me signals") as a rich source of nutrients for phagocytes during the digestion process ("digest-me"), such as amino acids, nucleotides, lipids, and carbohydrates. In recent years, several studies have contributed to unraveling the impact of the different stages of the efferocytosis process on regulating metabolic pathways that support the continuous phagocytosis of apoptotic cells, the activation profile, and the effector functions of phagocytes. In this review, we discuss the impact of efferocytosis on immune cells during homeostasis and infectious diseases, and in the metabolic reprogramming on phagocyte activation. We also explore the role of efferocytosis during the clearance of apoptotic cells in different pathologies.
    DOI:  https://doi.org/10.1038/s41419-026-08431-8
  14. Cell Rep. 2026 Feb 25. pii: S2211-1247(26)00109-9. [Epub ahead of print]45(3): 117031
    Listeria-infected macrophages promote biomechanical alterations in endothelial cell monolayers for transmigration.
    Marie Muenkel, Kathryn Wright, Erva Keskin, Julio C Sánchez-Rendón, Aylin Balmes, Tilman E Schäffer, Felix Romer, Marco Lebtig, Dorothee Kretschmer, Peter Loskill, Serge Mostowy, Effie E Bastounis.
      Intracellular pathogens, such as Listeria monocytogenes (LM), manipulate host cells to spread from the initial infection site to distant organs through the bloodstream. For that, LM hijacks mononuclear phagocytes to traverse vascular endothelial cell (EC) linings, but how transmigration is regulated by ECs is poorly understood. Here, we show that LM infection profoundly alters EC biomechanical responses to macrophages (MΦs). Videomicroscopy revealed that EC-MΦ contact induces EC polarization, alignment, and reduced motility. However, only interactions with uninfected MΦs increased EC traction and monolayer stresses and barrier integrity. This biomechanical response is largely contact-dependent and significantly attenuated during infection, thus contributing to the enhanced rate of LM-infected MΦ transmigration. Consistently, in the zebrafish model, infection increased endothelial permeability and phagocyte extravasation. These findings reveal that LM infection overrides MΦ-induced endothelial barrier strengthening to promote pathogen dissemination, a biomechanical strategy that could be harnessed for infection control.
    Keywords:  CP: cell biology; CP: microbiology; Listeria monocytogenes; bacterial infection; cell adhesion; cell biomechanics; endothelial cells; host-pathogen interactions; infected macrophage; traction force microscopy; transmigration; vascular permeability; zebrafish model
    DOI:  https://doi.org/10.1016/j.celrep.2026.117031
  15. Nat Commun. 2026 Feb 25.
    A gated hydrophobic funnel within BAX binds bioactive lipids to potentiate pro-apoptotic function.
    Jesse D Gelles, Yiyang Chen, Mark P A Luna-Vargas, Ariele Viacava Follis, Md Abdullah Al Noman, Md Kabir, Stella G Bayiokos, Jarvier N Mohammed, Tara M Sebastian, Ngoc Dung Pham, Yi Shi, Jian Jin, Richard W Kriwacki, Jerry Edward Chipuk.
      Mitochondria maintain a distinct biochemical environment that cooperates with pro-apoptotic BAX and BH3‑only proteins (e.g., BIM) to promote mitochondrial outer membrane permeabilization (MOMP), the key event to initiate physiological and pharmacological forms of apoptosis. The sphingosine-1-phosphate metabolite 2-trans-hexadecenal (2t‑hexadecenal) is a bioactive lipid that supports BAX-dependent MOMP. Using integrated structural and computational approaches, we determine that 2t‑hexadecenal binds within a distinct, dynamic region-a hydrophobic cavity formed by core-facing residues of α5, α6, and gated by α8-we now term the "BAX actuating funnel" (BAF). Complementary biochemical and biophysical techniques reveal that 2t-hexadecenal non-covalently interacts with the BAF and cooperates with BIM to stimulate intramolecular activation of monomeric BAX prior to membrane association. BAX α8 mobility and proline 168-mediated allostery are critical determinants for 2t-hexadecenal synergy with BAX and BIM, as is alkenal length to stimulate BAF function. Collectively, this work imparts detailed molecular insights into how pro-apoptotic BCL-2 proteins and bioactive lipids non-covalently cooperate to initiate the mitochondrial pathway of apoptosis with implications for biological and therapeutic regulation.
    DOI:  https://doi.org/10.1038/s41467-026-69836-9
  16. bioRxiv. 2026 Feb 13. pii: 2026.02.11.705431. [Epub ahead of print]
    Hyperglycemia promotes maladaptive Dectin-1 signaling and impairs skin antifungal host defense.
    Dante E Reyna, Erin Davis, Ana C G Salina, Amondrea Blackman, Ruben Martinez-Barricarte, Amanda Doran, C Henrique Serezani.
      People with chronic hyperglycemia are more susceptible to fungal skin infections, but the mechanisms underlying their worse clinical outcomes remain unclear. Using both in vivo and in vitro models, we explored how hyperglycemia influences skin antifungal defenses and how GLP1 agonists might restore host defense in diabetic conditions. Hyperglycemic mice showed increased susceptibility to Candida albicans skin infections, with larger lesions and higher fungal loads at all time points tested. Histology revealed larger abscesses, more extensive myeloid cell infiltration, and poorer control of fungal invasion, associated with increased chemoattractant production on day 1 post-infection. Despite heightened inflammatory responses, macrophages and keratinocytes exposed to high glucose exhibit markedly impaired fungal ingestion. RNAseq analysis of C. albicans -infected dermal macrophages cultured in high glucose showed enrichment of genes related to antimicrobial effectors and the C-type lectin receptor pathway, including Clec7a (Dectin-1), while suppressing downstream signaling pathways required for effective phagocytosis. Pharmacologic blockade or genetic deletion of Dectin-1 restored fungal uptake under high-glucose conditions and improved host defense in vivo . Mechanistically, Dectin-1 signaling in hyperglycemia promoted increased prostaglandin E₂ (PGE₂) production via induction of microsomal Prostaglandin E Synthase-1 (mPGES-1), and inhibition of PGE₂ synthesis rescued deficient phagocytic function. Finally, treatment with the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide reduced lesion size, fungal burden, inflammation, and tissue damage in diabetic mice, linking metabolic control to restoration of innate immune function. These findings identify maladaptive innate immune sensing as a key mechanism underlying susceptibility to fungal infection in diabetes and reveal how metabolic stress converts antifungal recognition pathways into drivers of inflammatory dysfunction.
    DOI:  https://doi.org/10.64898/2026.02.11.705431
This page is being maintained by Thomas Krichel. It was last updated on 2026‒03‒09 at 10:31.