Identification of an inhibitory budding signal that blocks the release of HIV particles and exosome/microvesicle proteins.
Identification of an inhibitory budding signal that blocks the release of HIV particles and exosome/microvesicle proteins.
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DOI：
10.1091/mbc.e10-07-0625
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发表时间：
2011-03-15
影响因子：
3.3
通讯作者：
Gould SJ
中科院分区：
文献类型：
--
作者：
Gan X;Gould SJ
我们确定并表征了抑制性出芽信号，其主要作用是阻止病毒和非病毒蛋白质的出芽，并损害几种经典的出芽缺陷型HIV突变体的出芽。这些发现扩展了我们对EMV生物发生的理解，并解决了一些以前关于HIV萌芽的矛盾观察。 动物细胞从内体和质膜上出芽外泌体和微泡（EMV）。高阶寡聚化和质膜结合的组合是将不同蛋白质靶向到EMV和逆转录病毒颗粒中的阳性出芽信号。在这里，我们描述了一种抑制性出芽信号（IBS）从人类免疫缺陷病毒（HIV）Gag蛋白。这种IBS在Gag的间隔肽2（SP2）结构域中被鉴定，通过SP2的C-末端暴露被激活，并且介导HIV的p6缺陷和PTAP缺陷株的严重出芽缺陷。这种IBS还损害CD 63和其他几种病毒和非病毒EMV蛋白的出芽。IBS不会阻止货物输送到质膜，这是EMV和病毒萌芽的主要部位。然而，IBS确实抑制EMV货物蛋白和VPS 4 B之间的相互作用，VPS 4 B是转运（ESCRT）机制所需的内体分选复合物的组分。两者合计，这些结果表明，抑制信号可以阻止蛋白质和病毒出芽，提高ESCRT机制在EMV生物发生中发挥作用的可能性，并揭示了p6结构域和PTAP基序在HIV颗粒生物发生中的作用。
We identify and characterize an inhibitory budding signal that acts dominantly to block the budding of otherwise budding-competent proteins, both viral and nonviral, and impairs the budding of several classic, budding-deficient HIV mutants. These findings expand our understanding of EMV biogenesis and resolve a number of previously paradoxical observations regarding the budding of HIV. Animal cells bud exosomes and microvesicles (EMVs) from endosome and plasma membranes. The combination of higher-order oligomerization and plasma membrane binding is a positive budding signal that targets diverse proteins into EMVs and retrovirus particles. Here we describe an inhibitory budding signal (IBS) from the human immunodeficiency virus (HIV) Gag protein. This IBS was identified in the spacer peptide 2 (SP2) domain of Gag, is activated by C-terminal exposure of SP2, and mediates the severe budding defect of p6-deficient and PTAP-deficient strains of HIV. This IBS also impairs the budding of CD63 and several other viral and nonviral EMV proteins. The IBS does not prevent cargo delivery to the plasma membrane, a major site of EMV and virus budding. However, the IBS does inhibit an interaction between EMV cargo proteins and VPS4B, a component of the endosomal sorting complexes required for transport (ESCRT) machinery. Taken together, these results demonstrate that inhibitory signals can block protein and virus budding, raise the possibility that the ESCRT machinery plays a role in EMV biogenesis, and shed new light on the role of the p6 domain and PTAP motif in the biogenesis of HIV particles.