γ-Secretase promotes membrane insertion of the human papillomavirus L2 capsid protein during virus infection.
γ-Secretase promotes membrane insertion of the human papillomavirus L2 capsid protein during virus infection.
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DOI：
10.1083/jcb.201804171
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发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Tsai B
中科院分区：
文献类型：
--
作者：
Inoue T;Zhang P;Zhang W;Goodner-Bingham K;Dupzyk A;DiMaio D;Tsai B
虽然人类乳头瘤病毒(HPV)导致许多人类癌症，但HPV感染的细胞基础仍然神秘。这篇手稿揭示了跨膜蛋白酶γ-分泌酶具有一种新的伴侣活性，促进HPVL2蛋白插入到内膜中。需要L2膜插入才能使感染进一步发展。尽管人类乳头瘤病毒(HPV)作为人类病原体很重要，但人们对它们进入细胞的了解很少。跨膜蛋白水解酶γ-分泌酶在人乳头状瘤病毒感染的早期阶段起着至关重要的作用，但γ-分泌酶在感染过程中的作用及其关键底物的定位尚不清楚。在这里，我们证明了γ分泌酶具有以前未知的伴侣功能，促进低pH依赖的HPVL2衣壳蛋白插入到内膜中。在膜插入后，L2招募胞浆逆转录聚体，使L2病毒基因组复合体进入逆行运输途径，并在感染的途中运输到高尔基体。虽然一小部分膜插入的L2也被γ-分泌酶切割，但这种蛋白分解事件似乎对HPV感染是必不可少的。我们的发现表明，γ分泌酶具有促进L2膜插入的活性，从而将病毒靶向高产的感染途径。
Although human papillomaviruses (HPVs) cause many human cancers, the cellular basis of HPV infection remains mysterious. This manuscript reveals that the transmembrane protease γ-secretase harbors a novel chaperone activity, promoting insertion of the HPV L2 protein into endosomal membranes. L2 membrane insertion is required for further progression of infection. Despite their importance as human pathogens, entry of human papillomaviruses (HPVs) into cells is poorly understood. The transmembrane protease γ-secretase executes a crucial function during the early stages of HPV infection, but the role of γ-secretase in infection and the identity of its critical substrate are unknown. Here we demonstrate that γ-secretase harbors a previously uncharacterized chaperone function, promoting low pH–dependent insertion of the HPV L2 capsid protein into endosomal membranes. Upon membrane insertion, L2 recruits the cytosolic retromer, which enables the L2 viral genome complex to enter the retrograde transport pathway and traffic to the Golgi en route for infection. Although a small fraction of membrane-inserted L2 is also cleaved by γ-secretase, this proteolytic event appears dispensable for HPV infection. Our findings demonstrate that γ-secretase is endowed with an activity that can promote membrane insertion of L2, thereby targeting the virus to the productive infectious pathway.
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DOI：
10.1083/jcb.93.1.97
发表时间：
1982-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fujiki Y;Hubbard AL;Fowler S;Lazarow PB
通讯作者：
Lazarow PB
肝素增加了独立于细胞表面蛋白聚糖的16型人乳头瘤病毒的感染性，并诱导L1表位暴露。
影响因子：
3.4
作者：
Cerqueira C;Liu Y;Kühling L;Chai W;Hafezi W;van Kuppevelt TH;Kühn JE;Feizi T;Schelhaas M
通讯作者：
Schelhaas M
影响因子：
5.4
作者：
Karanam, Balasubramanyam;Peng, Shiwen;Roden, Richard B. S.
通讯作者：
Roden, Richard B. S.
影响因子：
5.4
作者：
Giroglou, T;Florin, L;Sapp, M
通讯作者：
Sapp, M
抑制剂和底物对接位点之间的结构相互作用有助于深入了解人类 PS1 复合物的机制。
影响因子：
5.7
作者：
Li, Yi;Lu, Stephen Hsueh-Jeng;Tsai, Ching-Ju;Bohm, Christopher;Qamar, Seema;Dodd, Roger B.;Meadows, William;Jeon, Amy;McLeod, Adam;Chen, Fusheng;Arimon, Muriel;Berezovska, Oksana;Hyman, Bradley T.;Tomita, Taisuke;Iwatsubo, Takeshi;Johnson, Christopher M.;Farrer, Lindsay A.;Schmitt-Ulms, Gerold;Fraser, Paul E.;St George-Hyslop, Peter H.
通讯作者：
St George-Hyslop, Peter H.