Kaposi’s sarcoma (KS), a highly angiogenic and invasive vascular tumor, is the most common AIDS-associated cancer caused by KS-associated herpesvirus (KSHV) infection. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) contributes to KSHV-induced cell motility (PLoS Pathog. 15:e1007578, 2019). However, the role of vIRF1 in KSHV-induced angiogenesis remains unknown. Here, using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice, we show that vIRF1 promotes angiogenesis by upregulating CUB domain (for complement C1r/C1s, Uegf, Bmp1) containing protein 1 (CDCP1). Mechanistically, vIRF1 enhances the expression of transcription factor lymphoid enhancer-binding factor 1 (Lef1) and binds to Lef1 to promote CDCP1 transcription. Meanwhile, vIRF1 degrades metastasis suppressor CD82 through an ubiquitin–proteasome pathway by recruiting E3 ubiquitin ligase AMFR to CD82, which protects CDCP1 from CD82-mediated, palmitoylation-dependent degradation. CDCP1 activates AKT signaling, which is required for vIRF1-induced cell motility but not angiogenesis. Our results illustrate that, by hijacking Lef1 and CD82, vIRF1 upregulates CDCP1 to promote angiogenesis and cell invasion. These novel findings demonstrate the vIRF1 targets multiple cellular proteins and pathways to promote the pathogenesis of KS, which could be attractive therapeutic targets for KSHV-induced malignancies.

卡波西肉瘤 (KS) 是一种高度血管生成和侵袭性血管肿瘤，是由 KS 相关疱疹病毒 (KSHV) 感染引起的最常见的 AIDS 相关癌症。我们最近表明 KSHV 编码的病毒干扰素调节因子 1 (vIRF1) 有助于 KSHV 诱导的细胞运动 ( PLoS Pathog. 15:e1007578, 2019)。然而，vIRF1 在 KSHV 诱导的血管生成中的作用仍然未知。在这里，使用两种体内血管生成模型，包括小鸡绒毛尿囊膜测定 (CAM) 和小鼠基质胶栓血管生成测定，我们表明 vIRF1 通过上调含有蛋白质 1 的 CUB 域（用于补体 C1r/C1s、Uegf、Bmp1）来促进血管生成(CDCP1)。从机制上讲，vIRF1 增强转录因子淋巴增强子结合因子 1 (Lef1) 的表达并与 Lef1 结合以促进 CDCP1 转录。同时，vIRF1 通过泛素-蛋白酶体途径通过将 E3 泛素连接酶 AMFR 募集到 CD82 来降解转移抑制因子 CD82，从而保护 CDCP1 免受 CD82 介导的棕榈酰化依赖性降解。CDCP1 激活 AKT 信号，这是 vIRF1 诱导的细胞运动所必需的，但不是血管生成所必需的。我们的结果表明，通过劫持 Lef1 和 CD82，vIRF1 上调 CDCP1 以促进血管生成和细胞侵袭。这些新发现表明，vIRF1 靶向多种细胞蛋白和通路以促进 KS 的发病机制，这可能是 KSHV 诱导的恶性肿瘤的有吸引力的治疗靶点。