N-degron-mediated degradation of the proteolytically activated form of PKC-theta kinase attenuates its pro-apoptotic function

NWIPB OpenIR

	N-degron-mediated degradation of the proteolytically activated form of PKC-theta kinase attenuates its pro-apoptotic function
	Eldeeb, Mohamed A.; Zhou, Wenbin; Esmaili, Mansoore; Elgohary, Alaa M.; Wei, Hai; Fahlman, Richard P.
	2023
发表期刊	CELLULAR SIGNALLING
卷号	110
摘要	Cellular signalling cues lead to the initiation of apoptotic pathways and often result in the activation of caspases which in turn cause the generation of proteolytically generated protein fragments with new or altered functions. Mounting number of studies reveal that the activity of these proteolytically activated protein fragments can be counteracted via their selective degradation by the N-degron degradation pathways. Here, we investigate the proteolytically generated fragment of the PKC theta kinase, where we demonstrate the first report on the stability of this pro-apoptotic protein fragment. We have determined that the pro-apoptotic cleaved fragment of PKC-theta is unstable in cells because its N-terminal lysine targets it for proteasomal degradation via the N-degron degradation pathway and this degradation is inhibited by mutating the destabilizing N-termini, knockdown of the UBR1 and UBR2 E3 ligases. Tellingly, we demonstrate that the metabolic stabilization of the cleaved fragment of PKC-theta or inhibition of the N-degron degradation augments the apoptosis-inducing effect of staurosporine in Jurkat cells. Notably, we have unveiled that the cleaved fragment of PKC theta, per se, can induce apoptotic cell death in Jurkat T-cell leukemia. Our results expand the functional scope of mammalian N-degron degradation pathways, and support the notion that targeting N-degron degradation machinery may have promising therapeutic implications in cancer cells.
收录类别	SCIE
文献类型	期刊论文
条目标识符	http://210.75.249.4/handle/363003/61592
专题	中国科学院西北高原生物研究所
推荐引用方式 GB/T 7714	Eldeeb, Mohamed A.,Zhou, Wenbin,Esmaili, Mansoore,et al. N-degron-mediated degradation of the proteolytically activated form of PKC-theta kinase attenuates its pro-apoptotic function[J]. CELLULAR SIGNALLING,2023,110.
APA	Eldeeb, Mohamed A.,Zhou, Wenbin,Esmaili, Mansoore,Elgohary, Alaa M.,Wei, Hai,&Fahlman, Richard P..(2023).N-degron-mediated degradation of the proteolytically activated form of PKC-theta kinase attenuates its pro-apoptotic function.CELLULAR SIGNALLING,110.
MLA	Eldeeb, Mohamed A.,et al."N-degron-mediated degradation of the proteolytically activated form of PKC-theta kinase attenuates its pro-apoptotic function".CELLULAR SIGNALLING 110(2023).