ER‐to‐lysosome‐associated degradation of proteasome‐resistant ATZ polymers occurs via receptor‐mediated vesicular transport |
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Authors: | Timothy J Bergmann Andrea Raimondi Marisa Loi Tatiana Soldà Carmela Galli Rocco D'Antuono Diego Morone Alberto Danieli Paolo Paganetti Eelco van Anken Maurizio Molinari |
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Institution: | 1. Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Bellinzona, Switzerland;2. Department of Biology, Swiss Federal Institute of Technology, Zurich, Switzerland;3. Experimental Imaging Center, San Raffaele Scientific Institute, Ospedale San Raffaele, Milan, Italy;4. Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Ospedale San Raffaele, Milan, Italy;5. Laboratory for Biomedical Neurosciences, Neurocenter of Southern Switzerland, Taverne‐Torricella, Switzerland;6. School of Life Sciences, école Polytechnique Fédérale de Lausanne, Lausanne, Switzerland |
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Abstract: | Maintenance of cellular proteostasis relies on efficient clearance of defective gene products. For misfolded secretory proteins, this involves dislocation from the endoplasmic reticulum (ER) into the cytosol followed by proteasomal degradation. However, polypeptide aggregation prevents cytosolic dislocation and instead activates ill‐defined lysosomal catabolic pathways. Here, we describe an ER‐to‐lysosome‐associated degradation pathway (ERLAD) for proteasome‐resistant polymers of alpha1‐antitrypsin Z (ATZ). ERLAD involves the ER‐chaperone calnexin (CNX) and the engagement of the LC3 lipidation machinery by the ER‐resident ER‐phagy receptor FAM134B, echoing the initiation of starvation‐induced, receptor‐mediated ER‐phagy. However, in striking contrast to ER‐phagy, ATZ polymer delivery from the ER lumen to LAMP1/RAB7‐positive endolysosomes for clearance does not require ER capture within autophagosomes. Rather, it relies on vesicular transport where single‐membrane, ER‐derived, ATZ‐containing vesicles release their luminal content within endolysosomes upon membrane:membrane fusion events mediated by the ER‐resident SNARE STX17 and the endolysosomal SNARE VAMP8. These results may help explain the lack of benefits of pharmacologic macroautophagy enhancement that has been reported for some luminal aggregopathies. |
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Keywords: | endolysosomes ER‐phagy ER‐to‐lysosome‐associated degradation LC3 lipidation proteasome‐resistant aggregates |
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