title: ALIS are stress-induced protein storage compartments for substrates of the proteasome and autophagy.
abstract: Misfolded proteins can be directed into cytoplasmic aggregates such as aggresomes and dendritic cell aggresome-like induced structures (DALIS). DALIS were originally identified in lipopolysaccharide-stimulated dendritic cells and act as storage compartments for polyubiquitinated Defective Ribosomal Products (DRiPs) prior to their clearance by the proteasome. Here we demonstrate that ubiquitinated protein aggregates that are similar to DALIS, and not related to aggresomes, can be observed in several cell types in response to stress, including oxidative stress, transfection, and starvation. Significantly, both immune and nonimmune cells could form these aggresome-like induced structures (ALIS). Protein synthesis was essential for ALIS formation in response to oxidative stress, indicating that DRiP formation was required. Furthermore, puromycin, which increases DRiP formation, was sufficient to induce ALIS formation. Inhibition of either proteasomes or of autophagy interfered with ALIS clearance in puromycin treated cells. Autophagy inhibition enhanced ALIS formation under a variety of stress conditions. During starvation, ALIS formation in autophagy-deficient cells was only partially inhibited by protein synthesis inhibitors, indicating that both long-lived proteins and DRiPs can be targeted to ALIS. Together, these findings demonstrate that ALIS act as generalized stress-induced protein storage compartments for substrates of the proteasome and autophagy.
authors.affiliation: Infection, Immunity, Injury and Repair Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Szeto
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Kaniuk
authors.forename: Veronica
authors.initials: V
authors.lastname: Canadien
authors.forename: Rozalia
authors.initials: R
authors.lastname: Nisman
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshimori
authors.forename: David P
authors.initials: DP
authors.lastname: Bazett-Jones
authors.forename: John H
authors.initials: JH
authors.lastname: Brumell
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D019556:COS Cells; D002451:Cell Compartmentation / Q000502:physiology*; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D013312:Stress, Physiological / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D011506:Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex