State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, China.
Department of Geriatrics and Gerontology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
J Virol. 2021 Nov 9;95(23):e0108721. doi: 10.1128/JVI.01087-21. Epub 2021 Sep 8.
Envelope glycoproteins (Envs) of lentiviruses harbor unusually long cytoplasmic tails (CTs). Natural CT truncations always occur and are accompanied by attenuated virulence, but their effects on viral replication have not been fully elucidated. The Env in equine infectious anemia virus (EIAV) harbors the longest CT in the lentiviral family, and a truncated CT was observed in a live attenuated vaccine. This study demonstrates that CT truncation significantly increased EIAV production, as determined by comparing the virion yields from EIAV infectious clones in the presence and absence of the CT. A significant increase in a cleaved product from the CT-truncated Env precursor, but not the full-length Env, was observed. We further confirmed that the presence of the CT inhibited the cleavage of the Env precursor and found that a functional domain located at the C terminus was responsible for this function. Moreover, CT-truncated Env was mainly localized at the plasma membrane (PM), while full-length Env was mainly localized in the cytoplasm. The CT truncation caused a dramatic reduction in the endocytosis of Env. These results suggest that the CT can modulate the processing and trafficking of EIAV Env and thus regulate EIAV replication. The mature lentivirus envelope glycoprotein (Env) is composed of a surface unit (SU) and a transmembrane unit (TM), which are cleaved products of the Env precursor. After mature Env is heterodimerically formed from the cleavage of the Env precursor, it is trafficked to the plasma membrane (PM) for incorporation and virion assembly. Env harbors a long cytoplasmic tail (CT), which has been increasingly found to play multiple roles in the Env biological cycle. Here, we revealed for the first time that the CT of equine infectious anemia virus (EIAV) Env inhibits cleavage of the Env precursor. Simultaneously, the CT promoted Env endocytosis, resulting in weakened Env localization at the PM. We also validated that the CT could significantly decrease EIAV production. These findings suggest that the CT regulates the processing and trafficking of EIAV Env to balance virion production.
慢病毒的包膜糖蛋白 (Env) 具有异常长的细胞质尾巴 (CT)。天然 CT 截断总是发生，并且伴随着毒力减弱，但它们对病毒复制的影响尚未完全阐明。马传染性贫血病毒 (EIAV) 的 Env 具有慢病毒家族中最长的 CT，并且在活减毒疫苗中观察到截断的 CT。本研究表明，CT 截断显着增加了 EIAV 的产生，这是通过比较存在和不存在 CT 时 EIAV 感染性克隆的病毒粒子产量来确定的。观察到从 CT 截断的 Env 前体中切割产物的显着增加，但不是全长 Env。我们进一步证实 CT 的存在抑制了 Env 前体的切割，并发现位于 C 末端的功能域负责此功能。此外，CT 截断的 Env 主要定位于质膜 (PM)，而全长 Env 主要定位于细胞质中。CT 截断导致 Env 的内吞作用显着减少。这些结果表明 CT 可以调节 EIAV Env 的加工和运输，从而调节 EIAV 复制。成熟的慢病毒包膜糖蛋白 (Env) 由表面单元 (SU) 和跨膜单元 (TM) 组成，它们是 Env 前体的切割产物。成熟的 Env 在前体切割后异二聚形成，然后转运至质膜 (PM) 进行整合和病毒粒子组装。Env 具有长的细胞质尾巴 (CT)，已经越来越多地发现它在 Env 生物学周期中发挥多种作用。在这里，我们首次揭示了马传染性贫血病毒 (EIAV) Env 的 CT 抑制 Env 前体的切割。同时，CT 促进 Env 内吞作用，导致 Env 在 PM 上的定位减弱。我们还验证了 CT 可以显着降低 EIAV 的产生。这些发现表明 CT 调节 EIAV Env 的加工和运输，以平衡病毒粒子的产生。
