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- Title
Different Roles of p62 (SQSTM1) Isoforms in Keratin-Related Protein Aggregation.
- Authors
Somlapura, Meghana; Gottschalk, Benjamin; Lahiri, Pooja; Kufferath, Iris; Pabst, Daniela; Rülicke, Thomas; Graier, Wolfgang F.; Denk, Helmut; Zatloukal, Kurt
- Abstract
p62/Sequestosome-1 (p62) is a multifunctional adaptor protein and is also a constant component of disease-associated protein aggregates, including Mallory–Denk bodies (MDBs), in steatohepatitis and hepatocellular carcinoma. We investigated the interaction of the two human p62 isoforms, p62-H1 (full-length isoform) and p62-H2 (partly devoid of PB1 domain), with keratins 8 and 18, the major components of MDBs. In human liver, p62-H2 is expressed two-fold higher compared to p62-H1 at the mRNA level and is present in slightly but not significantly higher concentrations at the protein level. Co-transfection studies in CHO-K1 cells, PLC/PRF/5 cells as well as p62− total-knockout and wild-type mouse fibroblasts revealed marked differences in the cytoplasmic distribution and aggregation behavior of the two p62 isoforms. Transfection-induced overexpression of p62-H2 generated large cytoplasmic aggregates in PLC/PRF/5 and CHO-K1 cells that mostly co-localized with transfected keratins resembling MDBs or (transfection without keratins) intracytoplasmic hyaline bodies. In fibroblasts, however, transfected p62-H2 was predominantly diffusely distributed in the cytoplasm. Aggregation of p62-H2 and p62ΔSH2 as well as the interaction with K8 (but not with K18) involves acquisition of cross-β-sheet conformation as revealed by staining with luminescent conjugated oligothiophenes. These results indicate the importance of considering p62 isoforms in protein aggregation disease.
- Subjects
KERATIN; ADAPTOR proteins; PROTEINS; HEPATOCELLULAR carcinoma; OLIGOTHIOPHENES; SOCIAL interaction
- Publication
International Journal of Molecular Sciences, 2021, Vol 22, Issue 12, p6227
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms22126227