An L2 SUMO interacting motif is important for PML localization and infection of human papillomavirus type 16
An L2 SUMO interacting motif is important for PML localization and infection of human papillomavirus type 16
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DOI：
10.1111/cmi.12271
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发表时间：
2014-08-01
影响因子：
3.4
通讯作者：
Florin, Luise
中科院分区：
文献类型：
--
作者：
Bund, Timo;Spoden, Gilles A.;Florin, Luise
人乳头瘤病毒（HPV）可诱发皮肤和粘膜上的疣和癌症。HPV 16衣壳由蛋白质L1和L2组成。在细胞进入和病毒分解后，L2蛋白伴随病毒DNA进入宿主细胞核内的早幼粒细胞白血病核体（PML-NB），使病毒能够转录和复制。PML-NB的多个组分由基于共价SUMO修饰（SUMO化）或基于经由SUMO相互作用基序（SIM）的非共价SUMO相互作用的小泛素样修饰剂（SUMO）调节。我们在这里表明，HPV 16 L2包含至少一个SIM，这是至关重要的L2与SUMO 2在免疫沉淀和共定位与SUMO 2在PML-NB的相互作用。生物物理分析证实了直接L2相互作用与SUMO证实了潜在的L2-SUMO相互作用结构的分子动力学模拟中的识别。SIM的突变导致PML-NB处L2-DNA复合物的缺失和突变型HPV 16假病毒感染性的丧失。相反，我们发现L2 SUMO化对PML-NB和SUMO相互作用中的L2定位没有影响。我们的数据表明，L2 SIM对于L2与SUMO和/或SUMO化蛋白的相互作用非常重要，这对于将病毒DNA递送到PML-NB和有效的HPV感染是不可或缺的。
Human papillomaviruses (HPV) induce warts and cancers on skin and mucosa. The HPV16 capsid is composed of the proteins L1 and L2. After cell entry and virus disassembly, the L2 protein accompanies the viral DNA to promyelocytic leukaemia nuclear bodies (PML-NBs) within the host nuclei enabling viral transcription and replication. Multiple components of PML-NBs are regulated by small ubiquitin-like modifiers (SUMOs) either based on covalent SUMO modification (SUMOylation), or based on non-covalent SUMO interaction via SUMO interacting motifs (SIMs). We show here that the HPV16 L2 comprises at least one SIM, which is crucial for the L2 interaction with SUMO2 in immunoprecipitation and colocalization with SUMO2 in PML-NBs. Biophysical analysis confirmed a direct L2 interaction with SUMO substantiated by identification of potential L2-SUMO interaction structures in molecular dynamics simulations. Mutation of the SIM resulted in absence of the L2-DNA complex at PML-NB and in a loss of infectivity of mutant HPV16 pseudoviruses. In contrast, we found that L2 SUMOylation has no effect on L2 localization in PML-NBs and SUMO interaction. Our data suggest that the L2 SIM is important for L2 interaction with SUMO and/or SUMOylated proteins, which is indispensable for the delivery of viral DNA to PML-NBs and efficient HPV infection.