bims-nocaut Biomed News
on Non-canonical autophagy
Issue of 2025–06–29
two papers selected by
Quentin Frenger, University of Strasbourg



  1. Autophagy. 2025 Jun 26.
      Viral subversion of macroautophagy/autophagy is a well-established immune evasion strategy, with BCL2 homologs from γ-herpesviruses serving as prototypical inhibitors through BECN1 (beclin 1) sequestration. Yet the full spectrum of their functions remains incompletely understood. In our recent study, we uncovered a non-canonical role for the Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded BCL2 homolog (vBCL2) during late lytic replication. Unexpectedly, vBCL2 hijacks the host NDP kinase NME2/NM23-H2 to activate the mitochondrial fission GTPase DNM1L/DRP1, promoting mitochondrial fragmentation. This organelle remodeling dismantles MAVS-mediated antiviral signaling and facilitates virion assembly. A vBCL2 mutant unable to bind NME2 fails to induce fission or complete the viral lifecycle. These findings provide a long-sought answer to why vBCL2 is indispensable during lytic infection, and uncover a new immune evasion strategy centered on mitochondrial control. Our work expands the current view of virus-organelle interactions beyond canonical autophagy control and offers new targets for therapeutic intervention.
    Keywords:  DRP1; NM23-H2; herpesvirus; innate immunity; mitochondrial fission; vBCL2
    DOI:  https://doi.org/10.1080/15548627.2025.2522130
  2. bioRxiv. 2025 Apr 23. pii: 2025.04.21.649822. [Epub ahead of print]
      Activation of the cGAS-STING pathway stimulates innate immune signaling as well as LC3B lipidation and ubiquitylation at Golgi-related vesicles upon STING trafficking. Although ubiquitylation at these subcellular sites has been associated with regulating NF-κB-related innate immune signaling, the mechanisms of Golgi-localized polyubiquitin chain regulation of immune signaling is not well understood. We report here that the ubiquitin- and LC3B-binding proteins, TNIP1 and autophagy receptors p62, NBR1, NDP52, TAX1BP1, and OPTN associate with STING-induced ubiquitin and LC3B-labeled vesicles, and that p62 and NBR1 act redundantly in spatial clustering of the LC3B-labeled vesicles in the perinuclear region. We also find that while TBK1 kinase activity is not required for the recruitment of TNIP1 and the autophagy receptors, it also plays a role in sequestration of the LC3B-labeled vesicles. The ubiquitin binding domains, rather than the LC3B-interacting regions, of TNIP1 and OPTN are specifically important for their recruitment to Ub/LC3B-associated perinuclear vesicles, while OPTN is also recruited through a TBK1-dependent mechanism. Functionally, we find that TNIP1 and OPTN play a role in STING-mediated innate immune signaling, with TNIP1 acting as a significant negative regulator of both NF-κB- and Interferon-mediated gene expression. Together, these results highlight autophagy-independent mechanisms of autophagy receptors and TNIP1 with unanticipated roles in regulating STING-mediated innate immunity.
    DOI:  https://doi.org/10.1101/2025.04.21.649822