Covalent modification by SUMO is required for efficient disruption of PML oncogenic domains by Kaposi's sarcoma-associated herpesvirus latent protein LANA2
Covalent modification by SUMO is required for efficient disruption of PML oncogenic domains by Kaposi's sarcoma-associated herpesvirus latent protein LANA2
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DOI：
10.1099/vir.0.024984-0
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发表时间：
2011-01-01
影响因子：
3.8
通讯作者：
Rivas, Carmen
中科院分区：
文献类型：
--
作者：
Marcos-Villar, Laura;Campagna, Michela;Rivas, Carmen
多功能卡波西肉瘤相关疱疹病毒（KSHV）潜伏蛋白潜伏相关核抗原2（LANA 2）在KSHV诱导的B细胞恶性肿瘤中起关键作用。LANA 2增加小泛素样修饰物（SUMO）2-泛素修饰的PML的水平，并通过LANA 2中需要非共价SUMO相互作用结构域（SIM）的过程诱导PML致癌结构域（POD）的破坏。我们现在证明LANA 2在体外和潜伏性KSHV感染的B细胞中与SUMO 1和SUMO 2共价结合。我们发现，LANA 2 SIM突变体表现出轻微改变的SUMO化模式，这表明非共价SUMO相互作用代表了一种机制，用于确定SUMO底物识别和修饰。此外，几个赖氨酸残基被定位为SUMO缀合位点。一个sumoylation缺陷突变体表现出受损的能力，诱导破坏的POD，这表明，无论是直接结合或共价结合的SUMO部分可以作为一个桥梁LANA 2和其他SUMO修饰或SUMO相互作用的蛋白质之间的相互作用所需的破坏POD。
The multifunctional Kaposi's sarcoma-associated herpesvirus (KSHV) latent protein latency-associated nuclear antigen 2 (LANA2) has a critical role in KSHV-induced B-cell malignancies. LANA2 increases the level of small ubiquitin-like modifier (SUMO)2-ubiquitin-modified PML and induces the disruption of PML oncogenic domains (PODs) by a process that requires a non-covalent SUMO interaction domain (SIM) in LANA2. We now demonstrate that LANA2 is covalently conjugated to SUMO1 and SUMO2 both in vitro and in latently KSHV-infected B-cells. We show that a LANA2 SIM mutant exhibits a slightly altered sumoylation pattern, which suggests that non-covalent SUMO interactions represent a mechanism for determining SUMO substrate recognition and modification. In addition, several lysine residues were mapped as SUMO conjugation sites. A sumoylation-deficient mutant shows impaired ability to induce disruption of PODs, which suggests that either directly bound or covalently conjugated SUMO moieties may act as a bridge for interaction between LANA2 and other SUMO-modified or SUMO-interacting proteins required for disruption of PODs.