Hepatitis C virus modulates signal peptide peptidase to alter host protein processing.
Hepatitis C virus modulates signal peptide peptidase to alter host protein processing.
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丙型肝炎病毒调节信号肽肽酶以改变宿主蛋白质加工。
DOI：
10.1073/pnas.2026184118
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发表时间：
2021-06-01
影响因子：
11.1
通讯作者：
Okamoto T
中科院分区：
文献类型：
--
作者：
Hirano J;Yoshio S;Sakai Y;Songling L;Suzuki T;Itoh Y;Zhang H;Chen DV;Haga S;Oomori H;Kodama T;Maeda Y;Ono Y;Takahashi Y;Standley DM;Yamamoto M;Moriishi K;Moriya K;Kanto T;Takehara T;Koike K;Matsuura Y;Okamoto T
丙型肝炎病毒逃避免疫监视并导致慢性感染的机制尚不清楚。在这里，我们证明了丙型肝炎病毒核心蛋白干扰了由信号肽酶(SPP)催化的主要组织相容性复合体(MHC)I类的成熟，并通过HMG-CoA还原酶降解1同源基因而诱导降解。此外，我们还发现核心蛋白跨膜区与人巨细胞病毒US2蛋白同源，其跨膜区也以类似的方式针对SPP以损害MHC I类分子的表达。因此，我们的数据表明，SPP是DNA和RNA病毒损伤MHC I类分子的潜在靶点。免疫球蛋白是一种病毒蛋白，可阻止主要组织相容性复合体(MHC)I类的抗原提呈，从而逃避宿主的免疫识别。丙型肝炎病毒(丙型肝炎病毒)可以逃避免疫监视而诱导慢性感染；然而，感染丙型肝炎病毒的肝细胞如何影响免疫细胞和逃避免疫识别仍不清楚。在这里，我们证明了丙型肝炎病毒核心蛋白作为免疫转运蛋白的功能。它的表达干扰了信号肽酶(SPP)催化的MHC-I类分子的成熟，并通过HMG-CoA还原酶降解1同系物诱导其降解，从而损害了CD8+T细胞的抗原提呈。在丙型肝炎病毒核心转基因小鼠和慢性丙型肝炎患者的肝脏中，MHC I类分子的表达受到损害，但在获得持续病毒学应答的患者中恢复。最后，我们发现人类巨细胞病毒US2蛋白，在结构上与丙型肝炎病毒核心蛋白具有相似的跨膜区，以SPP为靶标来削弱MHC I类分子的表达。因此，SPP是DNA和RNA病毒损伤MHC I类分子的潜在靶点。
The mechanism by which hepatitis C virus (HCV) evades immune surveillance and causes chronic infection is unclear. We demonstrate here that HCV core protein interferes with the maturation of major histocompatibility complex (MHC) class I catalyzed by signal peptide peptidase (SPP) and induces degradation via HMG-CoA reductase degradation 1 homolog. In addition, we found that the core protein transmembrane domain is homologous to the human cytomegalovirus US2 protein, whose transmembrane region also targets SPP to impair MHC class I molecule expression in a similar manner. Therefore, our data suggest that SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses. Immunoevasins are viral proteins that prevent antigen presentation on major histocompatibility complex (MHC) class I, thus evading host immune recognition. Hepatitis C virus (HCV) evades immune surveillance to induce chronic infection; however, how HCV-infected hepatocytes affect immune cells and evade immune recognition remains unclear. Herein, we demonstrate that HCV core protein functions as an immunoevasin. Its expression interfered with the maturation of MHC class I molecules catalyzed by the signal peptide peptidase (SPP) and induced their degradation via HMG-CoA reductase degradation 1 homolog, thereby impairing antigen presentation to CD8+ T cells. The expression of MHC class I in the livers of HCV core transgenic mice and chronic hepatitis C patients was impaired but was restored in patients achieving sustained virological response. Finally, we show that the human cytomegalovirus US2 protein, possessing a transmembrane region structurally similar to the HCV core protein, targets SPP to impair MHC class I molecule expression. Thus, SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses.
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影响因子：
25.7
作者：
Conti, Fabio;Buonfiglioli, Federica;Brillanti, Stefano
通讯作者：
Brillanti, Stefano
影响因子：
16.6
作者：
Aizawa S;Okamoto T;Sugiyama Y;Kouwaki T;Ito A;Suzuki T;Ono C;Fukuhara T;Yamamoto M;Okochi M;Hiraga N;Imamura M;Chayama K;Suzuki R;Shoji I;Moriishi K;Moriya K;Koike K;Matsuura Y
通讯作者：
Matsuura Y
影响因子：
64.8
作者：
FRUH, K;AHN, K;YANG, Y
通讯作者：
YANG, Y
DOI：
10.1073/pnas.140217397
发表时间：
2000-07-18
影响因子：
11.1
作者：
Dantuma, NP;Heessen, S;Masucci, MG
通讯作者：
Masucci, MG
影响因子：
32.4
作者：
Boname, JM;Stevenson, PG
通讯作者：
Stevenson, PG