4.7 Article

The unfolded protein response transducer IRE1α promotes reticulophagy in podocytes

出版社

ELSEVIER
DOI: 10.1016/j.bbadis.2022.166391

关键词

Autophagy; Collagen IV; Endoplasmic reticulum stress; ERphagy; Reticulon-3; Sec23B

资金

  1. Canadian Institutes of Health Research [MOP-133492, PJ9-166216, PJ9-169678]
  2. Kidney Foundation of Canada
  3. Catherine McLaughlin Hakim Chair
  4. Fonds de recherche du Quebec - Sante
  5. Mexican National Council for Science and Technology (CONACYT)

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During ER stress, the IRE1 alpha pathway promotes RTN3L-mediated reticulophagy in podocytes and may play a cytoprotective role in glomerular diseases.
Glomerular diseases involving podocyte/glomerular epithelial cell (GEC) injury feature protein misfolding and endoplasmic reticulum (ER) stress. Inositol-requiring enzyme 1 alpha (IRE1 alpha) mediates chaperone production and autophagy during ER stress. We examined the role of IRE1 alpha in selective autophagy of the ER (reticulophagy). Control and IRE1 alpha knockout (KO) GECs were incubated with tunicamycin to induce ER stress and subjected to proteomic analysis. This showed IRE1 alpha-dependent upregulation of secretory pathway mediators, including the coat protein complex II component Sec23B. Tunicamycin enhanced expression of Sec23B and the reticulophagy adaptor reticulon-3-long (RTN3L) in control, but not IRE1 alpha KO GECs. Knockdown of Sec23B reduced autophagosome formation in response to ER stress. Tunicamycin stimulated colocalization of autophagosomes with Sec23B and RTN3L in an IRE1 alpha-dependent manner. Similarly, during ER stress, glomerular alpha 5 collagen IV colocalized with RTN3L and autophagosomes. Degradation of RTN3L and collagen IV increased in response to tunicamycin, and the turnover was blocked by deletion of IRE1 alpha; thus, the IRE1 alpha pathway promotes RTN3L-mediated reticulophagy and collagen IV may be an IRE1 alpha-dependent reticulophagy substrate. In experimental glomerulonephritis, expression of Sec23B, RTN3L, and LC3-II increased in glomeruli of control mice, but not in podocyte-specific IRE1 alpha KO littermates. In conclusion, during ER stress, IRE1 alpha redirects a subset of Sec23B-positive vesicles to deliver RTN3L-coated ER fragments to autophagosomes. Reticulophagy is a novel outcome of the IRE1 alpha pathway in podocytes and may play a cytoprotective role in glomerular diseases.

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