Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
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SHR Neuro Krebs Kardio Lipid Stoffw Microb
Somlapura, M; Gottschalk, B; Lahiri, P; Kufferath, I; Pabst, D; Rülicke, T; Graier, WF; Denk, H; Zatloukal, K.
Different Roles of p62 (SQSTM1) Isoforms in Keratin-Related Protein Aggregation.
Int J Mol Sci. 2021; 22(12):
Doi: 10.3390/ijms22126227
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- Führende Autor*innen der Med Uni Graz
- Somlapura Meghana
- Zatloukal Kurt
- Co-Autor*innen der Med Uni Graz
- Denk Helmut
- Gottschalk Benjamin
- Graier Wolfgang
- Kufferath Iris
- Pabst Daniela
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- 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.
- Find related publications in this database (Keywords)
- p62 isoforms
- keratins
- protein aggregation
- protein aggregation diseases