bims-nocaut 2025-11-09 papers

Issue of 2025–11–09
three papers selected by
Quentin Frenger, University of Strasbourg

Proc Natl Acad Sci U S A. 2025 Nov 11. 122(45): e2501953122

ENKD1 attenuates antibacterial immunity by facilitating TRIM21-mediated RUBCN degradation to suppress LC3-associated phagocytosis.

Caimeng Song, Lulu Sun, Jie Wang, Shujun Liu, Wenqing Xu, Cai Zhang, Jun Zhou, Tianliang Li, Yan Li.

Microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP) plays a critical role in host defense against invading pathogens, including Listeria monocytogenes (Listeria. monocytogenes), Salmonella typhimurium (S. typhimurium), and Francisella novicida (F. novicida). However, the precise regulatory mechanisms controlling LAP remain poorly understood. Here, we identify enkurin domain-containing protein 1 (ENKD1) as a key negative regulator of LAP during infection with these pathogens. Macrophages infected with L. monocytogenes (10403S), S. typhimurium (ATCC14028), or F. novicida (U112) exhibit significant ENKD1 downregulation. ENKD1-deficient macrophages display enhanced antibacterial activity, characterized by increased LAP, higher reactive oxygen species production, enhanced LC3 lipidation on phagosomes, and improved phagosome-lysosome fusion. In vivo, ENKD1-deficient mice exhibited improved bacterial clearance in the liver and spleen, with notable survival benefits. Mechanistically, ENKD1 interacts with the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21), which mediates degradation of Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (RUBCN) through K48-linked polyubiquitination, thereby dampening RUBCN's role in LAP. Our findings reveal an ENKD1-TRIM21-RUBCN axis that suppresses LAP, providing insights into antibacterial immune regulation and suggesting potential therapeutic strategies to enhance host defense against intracellular pathogens.

Keywords: ENKD1; LC3-associated phagocytosis; RUBCN; TRIM21; antibacterial immunity

DOI: https://doi.org/10.1073/pnas.2501953122

Cell Rep. 2025 Nov 03. pii: S2211-1247(25)01256-2. [Epub ahead of print]44(11): 116485

Identification of ATG7 as a protein ATG8ylation substrate.

Huazhong Xie, Jiahui Long, Yijun Huang, Yao Wang, Peiqing Liu, Min Li.

Protein ATG8ylation is a post-translational modification where ubiquitin-like protein LC3/ATG8 forms covalent conjugation with cellular proteins, a process reversed by ATG4. In contrast to the well-characterized ATG8 lipidation/membrane ATG8ylation, research on protein ATG8ylation remains limited. In this study, we identify deconjugation-resistant LC3B Q116A and F80A/L82A mutants as tools for protein ATG8ylation. We demonstrate that protein ATG8ylation depends exclusively on ATG4, ATG3, and ATG7. Tandem affinity purification-mass spectrometry reveals ATG7 as a substrate of protein ATG8ylation with K140 as its modification site. We show that protein ATG8ylation of ATG7 forms a mono-LC3B conjugate, while ATG3 undergoes lysine-dependent, mixed-linkage poly-LC3B chains. ATG7 and ATG3 function as E1 and E2 enzymes in protein ATG8ylation, potentially cooperating with E3 ligases. Notably, endogenous ATG7 ATG8ylation attenuates autophagy by disrupting its interaction with ATG3. These findings highlight ATG7 as both a central catalytic enzyme and key substrate in autophagy regulation through protein ATG8ylation.

Keywords: ATG3; ATG4; ATG7; CP: molecular biology; LC3 lipidation; autophagy; deconjugation-resistant; modification site; post-translational modification; protein ATG8ylation

DOI: https://doi.org/10.1016/j.celrep.2025.116485

Traffic. 2025 Oct;26(10-12): e70022

Beyond the Secretory Pathway: New Insights Into Protein Release.

In eukaryotes, protein secretion plays essential roles in intercellular communications and extracellular niche-building. Protein secretion generally requires a signal sequence that targets cargos to the canonical secretory pathway consisting of the endoplasmic reticulum (ER), the Golgi apparatus, plasma membrane, and vesicles moving between these compartments. However, cytoplasmic proteins lacking signal sequences (e.g., IL1β, Acb1, FGF2) have been detected, and many have defined functions in the extracellular space, suggesting unconventional protein secretion (UcPS) via alternative pathways. In recent years, scientists have uncovered many new UcPS paradigms, reporting a plethora of mechanisms that collectively form a new field. The inaugural Cold Spring Harbor Asia (CSHA) conference on "Molecular Mechanisms and Physiology of Unconventional Secretion" is the first meeting to bring these researchers together, providing a collegial platform for information sharing at this exciting frontier of cell biology research.

Keywords: CUPS; autophagy; extracellular vesicle; lysosome; stress adaptation; unconventional protein secretion

DOI: https://doi.org/10.1111/tra.70022