1. The N-terminal sequence of murine PRMT5 variant 2 is required for Hsp70 interaction and CHIP ligase-mediated degradation
- Author
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Weizhe Lu, Jun-Dal Kim, Hayase Mizukami, Saori Tabara, Keiji Kimura, Chulwon Kwon, and Akiyoshi Fukamizu
- Subjects
0301 basic medicine ,Male ,Protein-Arginine N-Methyltransferases ,Ubiquitin-Protein Ligases ,Biophysics ,Protein degradation ,Biochemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Heat shock protein ,Histone H2A ,Animals ,Humans ,HSP70 Heat-Shock Proteins ,Molecular Biology ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,chemistry.chemical_classification ,DNA ligase ,Chemistry ,Protein arginine methyltransferase 5 ,Cell Biology ,Methylation ,Cell biology ,Hsp70 ,Mice, Inbred C57BL ,030104 developmental biology ,HEK293 Cells ,Proteasome ,030220 oncology & carcinogenesis ,Female - Abstract
Protein arginine methyltransferase PRMT5 synthesizes the symmetric dimethylarginine in nuclear and cytoplasmic proteins such as histone H2A, H4 and several non-histone proteins that are required for a variety of biological processes. Currently, two splice variants (v1 and v2) of murine PRMT5 have been deposited in the NCBI sequence database, in which PRMT5-v1 and -v2 contain different 33 and 16 amino acids at the N-terminal sequences, respectively. Here we showed that murine PRMT5-v1 is stable, but PRMT5-v2 is constantly degraded through both the ubiquitin proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) in an N-terminal sequence-dependent manner. Furthermore, inhibition of UPS and ALP elevated the stability of PRMT5-v2 that made it localized in the nucleus and the cytoplasm. In addition, PRMT5-v2 exhibited the enzyme activity to catalyze histone H2A and H4 methylation. Notably, we found that the heat shock protein (Hsp) 70 specially recognizes the N-terminal sequence of PRMT5-v2 and the carboxyl terminus of Hsp70-interacting protein (CHIP) is required for poly-ubiquitination and the degradation of PRMT5-v2. These results suggest that Hsp70/CHIP chaperone-mediated protein degradation system is crucial in the regulation of PRMT5-v2 turnover, which has the potential to balance the symmetrical arginine dimethylation in cells.
- Published
- 2019