bims-nocaut 2026-03-29 papers

J Microbiol Immunol Infect. 2026 Mar 17. pii: S1684-1182(26)00039-3. [Epub ahead of print]

Inhibition of mitochondrial ROS turns LC3-associated phagocytosis to autophagy upon resveratrol treatment for group A Streptococcus clearance in endothelial cells.

Yi-Lin Cheng, Marcia Shu-Wei Su, Chen-Chieh Liao, Ting-Wei Chang, Yi-Chun Hsieh, Shiou-Ling Lu, Hiroko Omori, Takeshi Noda, Ying-Ling Chu, Chia-Ling Chen, Yee-Shin Lin, Jiunn-Jong Wu.

BACKGROUND: Group A Streptococcus (GAS; Streptococcus pyogenes), which causes a broad spectrum of diseases, has been found to invade cells to avoid host immune clearance and antibiotic killing. Our previous findings have shown that the virulence factors of GAS-NAD-glycohydrolase depletes intracellular NAD+ to inhibit xenophagy, and streptolysin O increases the production of intracellular reactive oxygen species (ROS) to promote ineffective LC3-associated phagocytosis (LAP), thereby impairing GAS clearance in endothelial cells. However, how endothelial cells counteract these strategies for GAS clearance has yet to be comprehensively investigated.
METHODS: We therefore speculated that resveratrol (RSV), a potent antioxidant and NAD+-dependent deacetylase-sirtuin activator, could be a potential antibacterial drug upon GAS infection in endothelial cells. To investigate the effect and the underlying mechanism of RSV on GAS infection, RSV was supplemented to human microvascular endothelial cell line-1 (HMEC-1) upon GAS infection, followed by detection of bacterial growth and examination the cellular regulation to LAP and xenophagy pathway.
RESULTS: RSV significantly inhibited intracellular GAS multiplication in endothelial cells through increasing acidification and double-membrane formation of LC3-positive GAS-containing vacuoles. RSV upregulated the expression of autophagy-related proteins but downregulated the LAP-related proteins in GAS-infected endothelial cells. Knockdown of sirtuin 3 (SIRT3) dismissed the effect of RSV on enhancement of autophagic clearance of GAS and suppression of mtROS, which may participate in regulation of acidification of LC3-positive GAS-containing vacuoles and LAP-related proteins expression.
CONCLUSION: RSV promotes intracellular GAS clearance in endothelial cells by shifting the ineffective LAP pathway to functional xenophagy through SIRT3-mediated inhibition of mtROS.

Keywords: Autophagy; Group A Streptococcus (GAS); LC3-Associated phagocytosis (LAP); Mitochondrial reactive oxygen species (mtROS); Resveratrol (RSV); Sirtuin 3 (SIRT3)

DOI: https://doi.org/10.1016/j.jmii.2026.03.006

bioRxiv. 2026 Mar 06. pii: 2026.03.04.709622. [Epub ahead of print]

Rubicon modulates neuroimmune responses following traumatic brain injury.

Sagarina Thapa, Amir Mehrabani-Tabari, Olivia Pettyjohn-Robin, Dexter Ph Nguyen, Mehari M Weldemariam, Chinmoy Sarkar, Maryam Khan, Maureen A Kane, Marta M Lipinski.

Traumatic brain injury (TBI) elicits robust neuroinflammation and oxidative stress, coupled with an acute inhibition of macro-autophagy (autophagy) in neurons and microglia. Rubicon ( Rubcn ), a Beclin1 interacting protein that suppresses autophagy and mediates LC3-associated phagocytosis and endocytosis (LAP/LANDO), influences inflammatory signaling in metabolic, neurodegenerative, and inflammaging diseases; yet its role in acquired brain injury has not been defined. Using a controlled cortical impact model, we investigated the role of Rubicon in acute neuroinflammatory responses following injury by comparing wild-type and Rubcn -mutant mice. Bulk-RNA sequencing of injured cortex revealed attenuated induction of inflammatory pathways and reduced activation of pro-inflammatory microglial/macrophage phenotype in injured Rubcn -mutant mice. Rubcn -mutant mice demonstrated less pronounced inhibition of autophagy during the acute phase of injury. Although the inflammatory dicerences were transient, Rubicon mutant mice exhibited improved motor coordination and gait stability during recovery. Proteomic analyses revealed the presence of a truncated Rubicon protein in the mutant mice and identified the negative regulator of reactive oxygen species (NRROS) as a novel interactor of Rubicon. Consistent with this interaction, Rubcn -mutant mice displayed markedly reduced oxidative damage, indicated by decreased lipid peroxidation after injury. Together, these findings indicate that Rubicon promotes acute neuroinflammatory and oxidative stress responses following TBI by modulating autophagy and ROS production. Rubicon mediated pathways may serve as therapeutic targets that ocer a neuroprotective strategy to improve outcomes after TBI.

DOI: https://doi.org/10.64898/2026.03.04.709622

bioRxiv. 2026 Mar 16. pii: 2026.03.13.711659. [Epub ahead of print]

Full length TECPR1 displays 'cis' Dysferlin domain architecture.

Ernest A Okertchiri, John B Miles, C Keith Cassidy, Adam L Yokom.

Tectonin Beta-Propeller Repeat containing 1 (TECPR1) is an essential regulator of a noncanonical autophagy pathway known as Sphingomyelin TECPR1 induced LC3 lipidation (STIL). TECPR1 forms an E3-like ligase complex and recognizes exposed sphingomyelin on damaged membranes. TECPR1 contains five folded domains however the structural basis for TECPR1 function has remained unresolved. Here, we report the first structure of full length TECPR1 resolved using cryo electron microscopy. TECPR1 forms an elongated hook shaped architecture that positions Dysferlin domains in a cis arrangement. Our structure uncovers an uncharacterized intramolecular interface between tectonin repeat 1 and PH domains. This interaction forms a stabilizing bridge that contributes to the orientation of the DysF domains. Molecular dynamics simulations further demonstrate that TECPR1 maintains the overall structural arrangement during membrane association. Our data provide a structural framework for how TECPR1 domain arrangement corresponds with membrane binding.

DOI: https://doi.org/10.64898/2026.03.13.711659

Trends Cell Biol. 2026 Mar 25. pii: S0962-8924(26)00033-4. [Epub ahead of print]

Repair condensates and lipid domains in lysosome integrity.

Claudio Bussi, Weiping Li.

Lysosomes are sophisticated signaling hubs whose function depends on membrane integrity. A breach of this barrier, known as lysosomal membrane permeabilization, triggers inflammation and cell death, driving pathologies from lysosomal storage disorders to neurodegeneration. Cells counter membrane damage with diverse repair mechanisms, including endosomal sorting complexes required for transport machinery, sphingomyelin scrambling, annexin-mediated scaffolding, lipid transport, and stress granule plugging. This diversity suggests singular strategies are insufficient, posing an 'orchestration challenge' regarding precise initiation, spatial organization, and temporal coordination. This opinion article proposes that biomolecular condensation, initiated by damage cues, acts as a primary organizing principle. We suggest lysosomal injury nucleates de novo 'repair condensates' that stabilize compromised membranes and serve as recruitment and organizational hubs for repair machinery.

Keywords: biomolecular condensates; lipids; lysophagy; lysosomes; membrane damage

DOI: https://doi.org/10.1016/j.tcb.2026.03.002

Annu Rev Biochem. 2026 Mar 25.

The Human Autophagy Core Complexes.

James H Hurley.

The autophagy core machinery carries out the fundamental reactions of autophagosome biogenesis across all forms of bulk and selective macroautophagy. In humans, the core complexes consist of the ULK1 complex (ULK1C), the class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1), the ATG8 proteins and the ATG8ylation machinery, the phosphatidylinositol 3-phosphate (PI3P)-sensing WIPI proteins, the lipid transporter ATG2, and the lipid scramblase and initiation scaffold ATG9. These complexes form a web of interactions that can be initiated by clustering of the FIP200 subunit of ULK1C but also by PI3KC3-C1 or WIPI2. Upon autophagy induction, these interactions are intensified by feed-forward signaling loops. These loops are amplified by WIPI-PI3P interactions and the conjugation of ATG8 proteins to the membrane by the ATG12-ATG5-ATG16L1 complex. Autophagosomes are seeded by ATG9 vesicles, which accrue initiation machinery on their surface and dock onto a PI3P-positive domain of the endoplasmic reticulum known as the omegasome. The omegasome contact site is the focal point for autophagosome growth, which is fed by lipid transport through the ATG2 bridge-like lipid transporter. The core complexes function in a dynamic manner, which makes autophagy vulnerable to stalling when dynamism fails. Disassembly and dissociation of the machinery, which is promoted at least in part by ULK1, is likely to be as important as assembly.

DOI: https://doi.org/10.1146/annurev-biochem-072425-030036

Cell. 2026 Mar 25. pii: S0092-8674(26)00267-9. [Epub ahead of print]

STING signaling modulation by COPII cargo recognition.

Heng Lyu, Cong Xing, Wanwan Huai, Kun Song, Devon Jeltema, Hui Zhang, Xuewu Zhang, Nan Yan.

Stimulator of interferon genes (STING) activation requires coat protein complex II (COPII)-mediated endoplasmic reticulum (ER) exit, but the mechanism remains elusive. Here, we identify EEΦxΦ (339EEVTV343 in human STING) as the ER-exit motif recognized by SEC24 homolog C (SEC24C). Using AlphaFold3, we present a predicted structure of SEC24C binding to a STING dimer, revealing the EEΦxΦ motif in a previously structurally unresolved region. Mutations in this motif or the SEC24C cargo-binding site disrupt STING trafficking and signaling. Our findings support a STING oligomerization and avidity threshold model that explains regulated ER exit. The EEΦxΦ motif is conserved in vertebrate STING homologs and is sufficient to mediate ER exit of unrelated proteins. Interestingly, the STING ER-exit motif is suboptimal compared with known SEC24C cargos, which is crucial for preventing immune overactivation. An engineered "super-ER-exit" STING is constitutively active and induces potent antitumor immunity. Tandem repeats of this motif competitively inhibit endogenous STING signaling. Collectively, this study elucidates the STING-ER-exit mechanism and presents strategies for modulating STING signaling.

Keywords: COPII; ER exit; SEC24C; STING; cancer; inflammation; vesicle trafficking

DOI: https://doi.org/10.1016/j.cell.2026.02.029