bims-nocaut Biomed News
on Non-canonical autophagy
Issue of 2025–05–04
two papers selected by
Quentin Frenger, University of Strasbourg
  1. The assembly of RAB22A/TMEM33/RTN4 initiates a secretory ER-phagy pathway.
  2. Potential therapeutic strategies targeting efferocytosis for inflammation resolution and tissue repair in inflammatory bowel disease.
  1. Cell Discov. 2025 Apr 29. 11(1): 41
    The assembly of RAB22A/TMEM33/RTN4 initiates a secretory ER-phagy pathway.
    Xueping Zheng, Dongmei Fang, Hao Shan, Beibei Xiao, Denghui Wei, Yingyi Ouyang, Lanqing Huo, Zhonghan Zhang, Yuanzhong Wu, Ruhua Zhang, Tiebang Kang, Ying Gao.
      Rafeesome, a newly identified multivesicular body (MVB)-like organelle, forms through the fusion of RAB22A-mediated ER-derived noncanonical autophagosomes with RAB22A-positive early endosomes. However, the mechanism underlying the formation of RAB22A-mediated noncanonical autophagosomes remains unclear. Herein, we report a secretory ER-phagy pathway in which the assembly of RAB22A/TMEM33/RTN4 induces the clustering of high-molecular-weight RTN4 oligomers, leading to ER membrane remodeling. This remodeling drives the biogenesis of ER-derived RTN4-positive noncanonical autophagosomes, which are ultimately secreted as TMEM33-marked RAB22A-induced extracellular vesicles (R-EVs) via Rafeesome. Specifically, RAB22A interacts with the tubular ER membrane protein TMEM33, which binds to the TM2 domain of the ER-shaping protein RTN4, promoting RTN4 homo-oligomerization and thereby generating RTN4-enriched microdomains. Consequently, the RTN4 microdomains may induce high curvature of the ER, facilitating the bud scission of RTN4-positive vesicles. These vesicles are transported by ATG9A and develop into isolation membranes (IMs), which are then anchored by LC3-II, a process catalyzed by the ATG12-ATG5-ATG16L1 complex, allowing them to grow into sealed RTN4 noncanonical autophagosome. While being packaged into these ER-derived intermediate compartments, ER cargoes bypass lysosomal degradation and are directed to secretory autophagy via the Rafeesome-R-EV route. Our findings reveal a secretory ER-phagy pathway initiated by the assembly of RAB22A/TMEM33/RTN4, providing new insights into the connection between ER-phagy and extracellular vesicles.
    DOI:  https://doi.org/10.1038/s41421-025-00792-2
  2. Cell Immunol. 2025 Apr 28. pii: S0008-8749(25)00042-5. [Epub ahead of print]411-412 104957
    Potential therapeutic strategies targeting efferocytosis for inflammation resolution and tissue repair in inflammatory bowel disease.
    Chaoquan Li, Wanting Liu, Aoni Fu, Haotian Yang, Guanghui Yi.
      Efferocytosis, the process by which apoptotic cells (ACs) are recognized and cleared by phagocytes, is a critical mechanism in maintaining intestinal immune homeostasis and promoting the resolution of inflammation. Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic intestinal inflammation, wherein defective efferocytosis contributes to the accumulation of ACs, secondary necrosis, and sustained mucosal damage. This review delineates the molecular mechanisms underlying efferocytosis and systematically examines its functional roles across five key intestinal phagocytic cell types: macrophages, dendritic cells (DCs), neutrophils, intestinal epithelial cells (IECs), and Paneth cells (PCs). Particular emphasis is placed on the dysregulation of efferocytosis capacity in IBD pathogenesis and the consequences of impaired apoptotic cell clearance in both professional and non-professional phagocytes. Furthermore, we evaluate emerging therapeutic strategies designed to restore or enhance efferocytosis, including modulation of macrophage polarization, LC3-associated phagocytosis pathways, nanotechnology-enabled delivery systems, and stem cell-based interventions. A comprehensive understanding of cell-type-specific efferocytosis in the intestinal microenvironment offers promising directions for the development of targeted, inflammation-resolving therapies for IBD.
    Keywords:  Dendritic cells; Efferocytosis; Inflammatory bowel disease; Intestinal epithelial cells; Macrophages; Neutrophils; Paneth cells
    DOI:  https://doi.org/10.1016/j.cellimm.2025.104957
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