The Deubquitination Of USP8 On CX43 And The Influence On Function Of CX43

Protein ubiquitinylation can regulate many functions including degradation,and deubiquitylating enzyme containing USP8 is one of the kay modulating factors.CX43 and GJIC composed mainly by CX43 are fundamental protein molecule and function of cells,regulating a lot of biological behaviours such as breast cancer metastasis.Ubiquitinylation is major triggering factor and choicing agent of CX43 degradation.So,exploring the detailed deubiquitinylation mechanism and degradation selection of CX43,and then detecting the influence on breast cancer metastasis,is of great importance in basic reasearch and latent clinical application.This topic is composed by two parts: firstly,we researched the detailed effects and mechanism of USP8 on CX43.Secondly,we specialized in the influence on cellular functions of CX43.In part one,we confirmed that USP8 can combine with CX43 directly,then deubiquitinylate CX43 after combination,which can result in the degradation inhibition of CX43 senquently.In the following deep-going research,we found out two major features of this degradation: 1,Degradation inhibition of CX43 after deubiquitinylation mainly due to blocking the autophagylysosome pathway.2,All the main ubiquitinylation modes of CX43,including multimonoubiquitinylation,K48-and K63-polyubiquitinylation,can be deubiquitinylate by USP8.Finally,based on the results from immunohistochemisty stain of clinical specimen,we revealed a positive corelation between USP8 and CX43.In part two,we first discovered at cellular level,this inhibition effect can do decrease the GJIC function,by the method of fluorescent dye transfer assay.Although USP8-knocking down brought minor changes in the proliferation and stemness features of breast cancer cells,it could increase the migration ability of breast cancer signifucantly,which being rescued by overexpress CX43 in the USP8-knocking down cells.Taken together,we conclude that USP8 via the deubiquitinylation to inhibit CX43 degradation through autophagy-lysosome pathway.The inhibition effect of CX43 degradation by USP8,can decrease the GJIC function,and increase the migration ability of breast cancer signifucantly.This effect probabely mean,USP8/CX43 play a key role in the breast cancer metastasis and dissemination,which deserve deepened research.