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Proteasomal and lysosomal clearance of faulty secretory proteins : ER-associated degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD) pathways

  • Fregno, Ilaria Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Molinari, Maurizio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    14.05.2019
Published in:
  • Critical reviews in biochemistry and molecular biology. - 2019, vol. 54, no. 2, p. 153-163
Autophagy
Endo-lysosomes
Endoplasmic reticulum (ER)
ER-associated degradation (ERAD)
ER-phagy
ER-phagy receptors
ER-to-lysosome-associated degradation (ERLAD)
Protein folding and quality control
RecovER-phagy
English About 40% of the eukaryotic cell’s proteins are inserted co- or post-translationally in the endoplasmic reticulum (ER), where they attain the native structure under the assistance of resident molecular chaperones and folding enzymes. Subsequently, these proteins are secreted from cells or are transported to their sites of function at the plasma membrane or in organelles of the secretory and endocytic compartments. Polypeptides that are not delivered within the ER (mis-localized proteins, MLPs) are rapidly destroyed by cytosolic proteasomes, with intervention of the membrane protease ZMPSTE24 if they remained trapped in the SEC61 translocation machinery. Proteins that enter the ER, but fail to attain the native structure are rapidly degraded to prevent toxic accumulation of aberrant gene products. The ER does not contain degradative devices and the majority of misfolded proteins generated in this biosynthetic compartment are dislocated across the membrane for degradation by cytosolic 26S proteasomes by mechanisms and pathways collectively defined as ERassociated degradation (ERAD). Proteins that do not engage ERAD factors, that enter aggregates or polymers, are too large, display chimico/physical features that prevent dislocation across the ER membrane (ERAD-resistant misfolded proteins) are delivered to endolysosome for clearance, by mechanisms and pathways collectively defined as ER-tolysosomes associated degradation (ERLAD). Emerging evidences lead us to propose ERLAD as an umbrella term that includes the autophagic and non-autophagic pathways activated and engaged by ERAD-resistant misfolded proteins generated in the ER for delivery to degradative endo-lysosomes.
Language
  • English
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Biology, life sciences
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https://n2t.net/ark:/12658/srd1319200
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