title: Cytosolic aggregates perturb the degradation of nontranslocated secretory and membrane proteins.
abstract: A wide range of diseases are associated with the accumulation of cytosolic protein aggregates. The effects of these aggregates on various aspects of normal cellular protein homeostasis remain to be determined. Here we find that cytosolic aggregates, without necessarily disrupting proteasome function, can markedly delay the normally rapid degradation of nontranslocated secretory and membrane protein precursors. In the case of mammalian prion protein (PrP), the nontranslocated fraction is recruited into preexisting aggregates before its triage for degradation. This recruitment permits the growth and persistence of cytosolic PrP aggregates, explaining their apparent "self-conversion" seen in earlier studies of transient proteasome inhibition. For other proteins, the aggregate-mediated delay in precursor degradation led to aggregation and/or soluble residence in the cytosol, often causing aberrant cellular morphology. Remarkably, improving signal sequence efficiency mitigated these effects of aggregates. These observations identify a previously unappreciated consequence of cytosolic aggregates for nontranslocated secretory and membrane proteins, a minor but potentially disruptive population the rapid disposal of which is critical to maintaining cellular homeostasis.
authors.affiliation: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. oishee.chakrabarti@saha.ac.in
authors.forename: Oishee
authors.initials: O
authors.lastname: Chakrabarti
authors.forename: Neena S
authors.initials: NS
authors.lastname: Rane
authors.forename: Ramanujan S
authors.initials: RS
authors.lastname: Hegde
mesh_terms: D000818:Animals; D002460:Cell Line; D003594:Cytoplasmic Granules / Q000378:metabolism*; D019085:Fluorescent Antibody Technique, Direct; D007976:Leupeptins / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000378:metabolism*; D011328:Prions / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011498:Protein Precursors / Q000378:metabolism*; D021382:Protein Sorting Signals; D055550:Protein Stability; D021381:Protein Transport; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D007976:Leupeptins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D011328:Prions; D061988:Proteasome Inhibitors; D011498:Protein Precursors; D021382:Protein Sorting Signals; D018019:Receptors, Corticotropin-Releasing Hormone; D011993:Recombinant Fusion Proteins; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde