bims-nocaut Biomed News
on Non-canonical autophagy
Issue of 2026–05–24
two papers selected by
Quentin Frenger, University of Strasbourg
  1. ATG5 in DCs attenuates anti-malarial cellular immune responses through interfering with TLR2-mediated CD209A/DC-SIGN expression.
  2. LC3B Mediated SETDB1-Accounted Alcoholic Steatohepatitis via Lipidation-Dependent LAP and Lipidation-Independent Nuclear Stabilization.
  1. Autophagy. 2026 May 22.
    ATG5 in DCs attenuates anti-malarial cellular immune responses through interfering with TLR2-mediated CD209A/DC-SIGN expression.
    Yongling Fan, Shiming Jiao, Hangyu Li, Yuanli Gao, Jiaqin Fang, Kun Zhang, Shuai Guo, Wenyue Xu, Taiping Liu.
      It is well established that the function of DCs (dendritic cells) is impaired during malaria infection; however, the underlying mechanisms responsible for this impairment remain poorly understood. In this study, we found that ATG5 (autophagy related 5) deficiency in DCs significantly suppressed the growth of malaria blood-stage parasites, and this effect was independent of both canonical and non-canonical macroautophagy/autophagy pathways in these cells. The reduced parasite growth observed in atg5Itgax/Cd11c-Cre+ mice was associated with an enhanced parasite-specific CD4+ T cell response, which provided crucial support for the functional activation of Plasmodium-specific CD8+ T cells. Mechanistically, ATG5 deficiency led to a marked increase in the expression of the phagocytic receptor CD209A/DC-SIGN on conventional DCs (cDCs), thereby enhancing their capacity to activate Plasmodium-specific CD4+ T cell responses. Furthermore, the expression of CD209A was mediated by the TLR2 (toll-like receptor 2) signaling pathway, which was significantly augmented in the absence of ATG5. Thus, we reveal a novel role for ATG5 in modulating anti-malarial cellular immune responses by influencing TLR2-mediated CD209A expression in cDCs. These findings not only enhance our understanding of impaired DC function during malaria infection but also provide valuable insights for the design of more effective malaria vaccines.
    Keywords:  ATG5; CD209A; CD4+ T cell responses; DCs; malaria parasite
    DOI:  https://doi.org/10.1080/15548627.2026.2679173
  2. Adv Sci (Weinh). 2026 May 19. e13189
    LC3B Mediated SETDB1-Accounted Alcoholic Steatohepatitis via Lipidation-Dependent LAP and Lipidation-Independent Nuclear Stabilization.
    Yi Zhang, Tan Wei, Jiahang Wu, Chuixu Lin, Dongbo Zhu, Yanhui Li, Shuting Shi, Shishun Huang, Leiming Jiang, Hongzhi Wang, Meiqi Song, Pengfei Gao, Xu Wu, Mingjian Fan, Chaofeng Wei, Qian Wang, Lihui Qu, Zhigang Wang.
      Alcohol-associated liver disease (ALD) progresses from steatosis to steatohepatitis, but the underlying mechanisms remain unclear. Here, we investigated SETDB1's role in ALD progression involving LC3B-mediated LC3-associated phagocytosis (LAP). SETDB1 expression was progressively downregulated in livers of alcohol-fed mice and ethanol-treated hepatocytes, correlating with disease severity. Setdb1 HKO mice exhibited accelerated ALD progression, developing severe steatosis, inflammation, and fibrosis even under pair-fed conditions, indicating SETDB1 deficiency enhances disease susceptibility to nutritional stressors. Mechanistically, SETDB1 acted as a transcriptional cofactor for ERG to promote Map1lc3b transcription. SETDB1 deficiency impaired LAP by disrupting Rubicon membrane localization, causing defective lipid droplet clearance and enhanced cGAS-STING activation. The ATG16L1 WD40 domain was essential for this LAP-mediated protection. LC3B restoration in Setdb1 HKO mice ameliorated steatosis, inflammation, and liver injury. Notably, the lipidation-deficient LC3B-G120A mutant failed to rescue steatosis but partially suppressed inflammation, revealing a lipidation-independent LC3B function. We demonstrate lipidated LC3B mediates cytoplasmic LAP-dependent lipid clearance, while non-lipidated LC3B translocates to the nucleus, reducing R-loop accumulation, preserving genomic stability, and restraining cGAS-STING-driven inflammation. Collectively, these findings define a protective SETDB1-ERG-LC3B axis restraining ALD progression and reveal dual LC3B functions, offering mechanistic insight and a potential therapeutic strategy for intercepting steatosis-to-steatohepatitis transition.
    Keywords:  LC3‐associated phagocytosis; SETDB1; alcohol‐associated liver disease; cGAS‐STING pathway; nuclear stability
    DOI:  https://doi.org/10.1002/advs.202513189
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