title: p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases.
abstract: Exposure of cells to stress, particularly oxidative stress, leads to misfolding of proteins and, if they are not refolded or degraded, to cytoplasmic protein aggregates. Protein aggregates are characteristic features of a variety of chronic toxic and degenerative diseases, such as Mallory bodies (MBs) in hepatocytes in alcoholic and non-alcoholic steatohepatitis, neurofibrillary tangles in neurons in Alzheimer's, and Lewy bodies in Parkinson's disease. Using 2D gel electrophoresis and mass spectrometry, we identified p62 as a novel MB component. p62 and cytokeratins (CKs) are major MB constituents; HSP 70, HSP 25, and ubiquitinated CKs are also present. These proteins characterize MBs as a prototype of disease-associated cytoplasmic inclusions generated by stress-induced protein misfolding. As revealed by transfection of tissue culture cells overexpressed p62 did not induce aggregation of regular CK filaments but selectively bound to misfolded and ubiquitinated CKs. The general role of p62 in the cellular response to misfolded proteins was substantiated by detection of p62 in other cytoplasmic inclusions, such as neurofibrillary tangles, Lewy bodies, Rosenthal fibers, intracytoplasmic hyaline bodies in hepatocellular carcinoma, and alpha1-antitrypsin aggregates. The presence of p62 along with other stress proteins and ubiquitin in cytoplasmic inclusions indicates deposition as aggregates as a third line of defense against misfolded proteins in addition to refolding and degradation.
authors.affiliation: Department of Pathology, Karl-Franzens University, Graz, Austria. kurt.zatloukal@kfunigraz.ac.at
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
authors.forename: Cornelia
authors.initials: C
authors.lastname: Stumptner
authors.forename: Andrea
authors.initials: A
authors.lastname: Fuchsbichler
authors.forename: Hans
authors.initials: H
authors.lastname: Heid
authors.forename: Martina
authors.initials: M
authors.lastname: Schnoelzer
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kleinert
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
authors.forename: Helmut
authors.initials: H
authors.lastname: Denk
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001254:Astrocytoma / Q000378:metabolism; D016466:CHO Cells; D016543:Central Nervous System Neoplasms / Q000378:metabolism; D006224:Cricetinae; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D007633:Keratins / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D051379:Mice; D019636:Neurodegenerative Diseases / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D013312:Stress, Physiological / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D011506:Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025801:Ubiquitin; D007633:Keratins