ABSTRACT

Avian leukosis virus subgroup J (ALV-J) generally induces hemangioma, myeloid leukosis, and immunosuppression in chickens, causing significant poultry industry economic losses worldwide. The unusual env gene of ALV-J, with low homology to other subgroups of ALVs, is associated with its unique pathogenesis. However, the exact molecular basis for the pathogenesis and oncogenesis of ALV-J is still not fully understood. In this study, ALV-J infection and the overexpression of Env could efficiently downregulate the phosphorylation of SHP-2 (pSHP-2) in vitro and in vivo. The membrane-spanning domain (MSD) in Env Gp37 was the functional domain responsible for pSHP-2 downregulation. Moreover, the overexpression of SHP-2 could effectively promote the replication of ALV-J, whereas knockout or allosteric inhibition of SHP-2 could inhibit ALV-J replication. In addition, the knockout of endogenous chicken SHP-2 could significantly increase the proliferation ability of DF-1 cells. All these data demonstrate that SHP-2 dephosphorylated by ALV-J Env could efficiently promote ALV-J replication, highlighting the important role of SHP-2 in the pathogenesis of ALV-J and providing a new target for developing antiviral drugs against ALV-J.

摘要

禽白血病病毒亚群 J (ALV-J) 通常会在鸡中诱发血管瘤、骨髓性白血病和免疫抑制，从而在全球范围内造成重大的家禽业经济损失。ALV-J的不寻常env基因与其他 ALV 亚群同源性低，与其独特的发病机制有关。然而，ALV-J 发病机制和肿瘤发生的确切分子基础仍不完全清楚。在这项研究中，ALV-J 感染和 Env 的过表达可以在体外和体内有效地下调 SHP-2 (pSHP-2) 的磷酸化. Env Gp37 中的跨膜结构域 (MSD) 是负责 pSHP-2 下调的功能结构域。此外，SHP-2的过表达可有效促进ALV-J的复制，而SHP-2的敲除或变构抑制可抑制ALV-J的复制。此外，内源性鸡SHP-2的敲除可显着提高DF-1细胞的增殖能力。这些数据表明，ALV-J Env去磷酸化的SHP-2可以有效促进ALV-J复制，凸显了SHP-2在ALV-J发病机制中的重要作用，为开发抗ALV-J抗病毒药物提供了新的靶点。 .