期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 293, 期 21, 页码 8275-8284出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA117.001315
关键词
ubiquitin ligase; ubiquitylation (ubiquitination); autophagy; connexin; deubiquitylation (deubiquitination); USP8; Cx43; ubiquitin; degradation; autophagy
资金
- 1000 Youth Elite Program
- Shanghai Jiao Tong University School of Medicine [15PJ1407400]
- Science and Technology Commission of Shanghai Municipality Grant [1402700]
- National Natural Science Foundation of China [81172505]
- Municipality Cross Research Foundation of Shanghai Jiao Tong University [YG2017QN49]
- Shanghai Municipality Commission of Health and Family Planning [201640006]
- Shanghai Pujiang Scholarship [15PJ1407400]
Connexin-43 (Cx43, also known as GJA1) is the most ubiquitously expressed connexin isoform in mammalian tissues. It forms intercellular gap junction (GJ) channels, enabling adjacent cells to communicate both electrically and metabolically. Cx43 is a short-lived protein which can be quickly degraded by the ubiquitin-dependent proteasomal, endolysosomal, and autophagosomal pathways. Here, we report that the ubiquitin-specific peptidase 8 (USP8) interacts with and deubiquitinates Cx43. USP8 reduces both multiple monoubiquitination and polyubiquitination of Cx43 to prevent autophagy-mediated degradation. Consistently, knockdown of USP8 results in decreased Cx43 protein levels in cultured cells and suppresses intercellular communication, revealed by the dye transfer assay. In human breast cancer specimens, the expression levels of USP8 and Cx43 proteins are positively correlated. Taken together, these results identified USP8 as a crucial and bona fide deubiquitinating enzyme involved in autophagy-mediated degradation of Cx43.
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