The Rictor/mTOR complex plays a pivotal role in a variety of cellular functions including cellular metabolism,cell proliferation and survival by phosphorylating Akt at Ser473 to fully activate the Akt kinase.However,i...The Rictor/mTOR complex plays a pivotal role in a variety of cellular functions including cellular metabolism,cell proliferation and survival by phosphorylating Akt at Ser473 to fully activate the Akt kinase.However,its upstream regulatory pathways as well as whether it has additional function(s)remain largely unknown.We recently reported that Rictor contains a novel ubiquitin E3 ligase activity by forming a novel complex with Cullin-1,but not with other Cullin family members.Furthermore,we identified SGK1 as its downstream target.Interestingly,Rictor,but not Raptor or mTOR,promotes SGK1 ubiquitination.As a result,SGK1 expression is elevated in Rictor^(–/–)MEFs.We further defined that as a feedback mechanism,Rictor can be phosphorylated by multiple AGC family kinases including Akt,S6K and SGK1.Phosphorylation of Rictor at the Thr1135 site did not affect its kinase activity towards phosphorylating its conventional substrates including Akt and SGK1.On the other hand,it disrupted the interaction between Rictor and Cullin-1.Consequently,T1135E Rictor was defective in promoting SGK1 ubiquitination and destruction.This finding further expands our knowledge of Rictor’s function.Furthermore,our work also illustrates that Rictor E3 ligase activity could be governed by specific signaling kinase cascades,and that misregulation of this process might contribute to SGK overexpression which is frequently observed in various types of cancers.展开更多
Virion infectivity factor（Vif） is one of the six accessory proteins of HIV-1 and is necessary for viral infectivity. Human Apolipoprotein B editing complex protein 3G（h-APOBEC3G） is a cytidine deaminase only expre...Virion infectivity factor（Vif） is one of the six accessory proteins of HIV-1 and is necessary for viral infectivity. Human Apolipoprotein B editing complex protein 3G（h-APOBEC3G） is a cytidine deaminase only expressed in ＂nonpermissive＂ cells and exhibits virus suppressive activity. With the aid of a Cullin-5 E3 ligase, Vif induces h-APOBEC3G degradation and with the destruction of this ligase, Vif is functionally inactive. Therefore, it is expected that blocking this E3 pathway would be a new therapeutic strategy against HIV-1 infection. In this article, the authors＇ took sequence alignment of the N-termini of Cullin-5 and three other members of the Cullin protein family, respectively. A set of small peptides has been synthesized based on the sequence comparison results and possible Vif-Cullin-5 interaction domains. Moreover, it has been demonstrated that several peptides can reduce virus infectivity in ＂nonpermissive＂ cells with a dose-responsive manner, but not in ＂permissive＂ cells. The results also indicate that the loss of viral infectivity may be because of the increase of APOBEC3G amount in the peptide-treated cells. It is concluded that peptides derived from Cullin-5 can block the APOBEC3G degradation induced by Vif and suppress HIV-1 infectivity. Therefore this study starts a novel strategy for the development of a new HIV-1 inhibitor.展开更多
基金supported in part by the DOD Prostate New Investigator award to W.W.NIH grant GM089763 to W.W.
文摘The Rictor/mTOR complex plays a pivotal role in a variety of cellular functions including cellular metabolism,cell proliferation and survival by phosphorylating Akt at Ser473 to fully activate the Akt kinase.However,its upstream regulatory pathways as well as whether it has additional function(s)remain largely unknown.We recently reported that Rictor contains a novel ubiquitin E3 ligase activity by forming a novel complex with Cullin-1,but not with other Cullin family members.Furthermore,we identified SGK1 as its downstream target.Interestingly,Rictor,but not Raptor or mTOR,promotes SGK1 ubiquitination.As a result,SGK1 expression is elevated in Rictor^(–/–)MEFs.We further defined that as a feedback mechanism,Rictor can be phosphorylated by multiple AGC family kinases including Akt,S6K and SGK1.Phosphorylation of Rictor at the Thr1135 site did not affect its kinase activity towards phosphorylating its conventional substrates including Akt and SGK1.On the other hand,it disrupted the interaction between Rictor and Cullin-1.Consequently,T1135E Rictor was defective in promoting SGK1 ubiquitination and destruction.This finding further expands our knowledge of Rictor’s function.Furthermore,our work also illustrates that Rictor E3 ligase activity could be governed by specific signaling kinase cascades,and that misregulation of this process might contribute to SGK overexpression which is frequently observed in various types of cancers.
基金the National Natural Science Foundation of China(No.30570363)Distinguished Young Scholars Fund of Jilin Province, China(No.20050112)the New Century Excellent Talents
文摘Virion infectivity factor（Vif） is one of the six accessory proteins of HIV-1 and is necessary for viral infectivity. Human Apolipoprotein B editing complex protein 3G（h-APOBEC3G） is a cytidine deaminase only expressed in ＂nonpermissive＂ cells and exhibits virus suppressive activity. With the aid of a Cullin-5 E3 ligase, Vif induces h-APOBEC3G degradation and with the destruction of this ligase, Vif is functionally inactive. Therefore, it is expected that blocking this E3 pathway would be a new therapeutic strategy against HIV-1 infection. In this article, the authors＇ took sequence alignment of the N-termini of Cullin-5 and three other members of the Cullin protein family, respectively. A set of small peptides has been synthesized based on the sequence comparison results and possible Vif-Cullin-5 interaction domains. Moreover, it has been demonstrated that several peptides can reduce virus infectivity in ＂nonpermissive＂ cells with a dose-responsive manner, but not in ＂permissive＂ cells. The results also indicate that the loss of viral infectivity may be because of the increase of APOBEC3G amount in the peptide-treated cells. It is concluded that peptides derived from Cullin-5 can block the APOBEC3G degradation induced by Vif and suppress HIV-1 infectivity. Therefore this study starts a novel strategy for the development of a new HIV-1 inhibitor.
