bims-nocaut 2025-12-14 papers

Issue of 2025–12–14
four papers selected by
Quentin Frenger, University of Strasbourg

Autophagy. 2025 Dec 08.

Trans-Golgi network-associated noncanonical autophagy depends on the V-ATPase-ATG16L1 axis and mediates IL1B secretion.

Jiahui Long, Huazhong Xie, Hao Shan, Ruoqing Chen, Jialing Zhong, Jiuge Tang, Dongmei Fang, Yao Wang, Peiqing Liu, Xiao-Ming Yin, Min Li.

Formation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3)-positive structures that does not require all of the core ATG (autophagy related) proteins is emerging in the process of noncanonical autophagy (NCA). While LC3 lipidation on endolysosomal membranes has been well characterized, the involvement of other membrane sources and the regulatory mechanisms governing LC3 lipidation in alternative forms of NCA remain poorly understood. Here, we demonstrate the occurrence of LC3 lipidation on the trans-Golgi network (TGN) platform. Different from canonical autophagosomes, these LC3-positive structures do not fuse with lysosomes, and fail to degrade long-lived proteins. In addition, the functional vacuolar-type H+-translocating ATPase (V-ATPase)-ATG16L1 axis is found to be essential for TGN-associated NCA. Notably, in this process, the cytosolic but not lysosomal V1 complex of the V-ATPase assembles at the TGN and plays a pivotal role in further induction of NCA. Eventually, IL1B/IL-1β (interleukin 1 beta) secretion is found to be efficiently enhanced by such TGN-associated NCA, independently of GSDM (gasdermin)-mediated pore formation. Thus, besides the known endolysosome-related NCA, we identify a distinct form of TGN-associated NCA mediated by the V-ATPase-ATG16L1 axis. Such NCA might work as a protein-transport route for the extracellular secretion of IL1B, revealing a mechanism linking Golgi-derived NCA to inflammatory cytokines release.

Keywords: ATG16L1; CASM; TGN; V-ATPase; membrane atg8ylation; unconventional protein secretion

DOI: https://doi.org/10.1080/15548627.2025.2601896

J Mycol Med. 2025 Dec 05. pii: S1156-5233(25)00061-7. [Epub ahead of print]36(1): 101598

The innate immune response to A. fumigatus in alveolar macrophages: Roles of LC3-associated phagocytosis, apoptosis and inflammation.

Yuqing Sun, Xiao Cui, Yulin Zhang.

Aspergillus fumigatus (A. fumigatus) has a life-threatening effect in immunocompromised populations, underscore the vital role played by the interplay between the host immune response and this fungal pathogen. Alveolar macrophage (AM) situated within the alveolar spaces serve as the primal immune cells to engage with inhaled Aspergillus conidia. These AMs deploy various strategies to resist A. fumigatus assaults. Their capacity to eliminate A. fumigatus is contingent upon LC3-associated phagocytosis (LAP), an immunological safeguard against microbial intrusions. Furthermore, the propensity for apoptosis fosters frequent inter-macrophage transfer of A. fumigatus, thereby facilitating control over conidia germination. The activation of inflammasomes and the subsequent release of cytokines and chemokines also constitutes a crucial defensive mechanism employed by AM against A. fumigatus invasions. This review delves into the intricate immune reactions and protective manners mounted by macrophages during A. fumigatus infection. Unraveling the interactions between the host immune system and A. fumigatus could pave the way for innovative therapeutic interventions.

Keywords: A. fumigatus; Apoptosis; Inflammatory response; LC3-associated phagocytosis; Macrophage

DOI: https://doi.org/10.1016/j.mycmed.2025.101598

Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2504528122

Molecular mechanisms underlying p62-dependent secretion of the Alzheimer-associated ubiquitin variant UBB+1.

Ajay R Wagh, Michael H Glickman.

UBB+1, a ubiquitin variant protein resulting from a frameshift in the ubiquitin-B gene, is a pathological hallmark of Alzheimer disease (AD). At the cellular level, UBB+1 disrupts the ubiquitin-proteasome system while inducing autophagy. Notably, UBB+1 itself is secreted via autophagosome-like vesicles. Here, we demonstrate that UBB+1 can be removed from the cell by degradative and secretory autophagy. Sequestosome 1 (SQSTM1)/p62 functions as a pivotal ubiquitin receptor for UBB+1, recognizing its ubiquitin domain and facilitating loading into autophagosomes. Oligomerization of SQSTM1/p62 was critical to isolate UBB+1 in bodies preventing its aggregation. Intriguingly, both gain- and loss-of-function SQSTM1/p62 suppressed UBB+1 secretion, causing intracellular retention: SQSTM1/p62 knockout led to UBB+1 accumulation in insoluble aggregates, while its overexpression promoted the formation of p62-UBB+1 bodies. We further identified distinct roles for SNARE-mediated membrane fusion in secretory autophagy of UBB+1. Specifically, the R-SNARE SEC22B and the Q-SNAREs Syntaxin-4 and SNAP23 participated in UBB+1 exocytosis. Disruption of SEC22B impaired the fusion of UBB+1-containing autophagosomes with the plasma membrane, reducing UBB+1 secretion without affecting its intracellular turnover. Inhibition of lysosomes partially stabilized UBB+1 indicating that degradation and secretion are complementary processes that determine the fate of UBB+1. This study elucidates the dual roles of autophagy in managing neurotoxic proteins, highlighting SQSTM1/p62 as a key mediator of UBB+1 trafficking and secretion. Although ubiquitin typically acts as a degradation signal, our findings reveal a rare instance of a ubiquitin-related protein driving secretory autophagy. These findings advance our understanding of cellular mechanisms underlying the clearance of misfolded proteins in neurodegenerative diseases.

Keywords: Alzheimer’s disease; autophagy; p62; trafficking; ubiquitin

DOI: https://doi.org/10.1073/pnas.2504528122