Identification of alternatively translated Tetherin isoforms with differing antiviral and signaling activities.
Identification of alternatively translated Tetherin isoforms with differing antiviral and signaling activities.
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DOI：
10.1371/journal.ppat.1002931
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发表时间：
2012-09
期刊：
影响因子：
6.7
通讯作者：
Bates P
中科院分区：
文献类型：
--
作者：
Cocka LJ;Bates P
Tetherin(BST-2/CD317/HM1.24)是一种干扰素诱导的跨膜蛋白，可限制多种囊膜病毒的释放。Tetherin活性和调控所需的重要特征存在于细胞质区域。在这里，我们证明了在培养的人类细胞系和原代细胞中都产生了两种异构体，它们来自细胞质结构域中高度保守的蛋氨酸残基的交替翻译起始。这两种异构体具有不同的生物学特性。短异构体(S-Tetherin)在长异构体(L-Tetherin)中缺少12个残基，对VPU介导的HIV-1VPU下调具有明显的抵抗力，因此更有效地限制了VPU存在下的HIV1病毒萌发。S-Tetherin VPU抗性可以通过长亚型中存在的丝氨酸-苏氨酸和酪氨酸基序的丢失来解释。相比之下，L-Tetherin异构体被发现是核因子-kappa B(NF-κB)信号的激活剂，而S-Tetherin不激活NF-κB。激活NF-κB需要在较长物种的细胞质尾部发现一个基于酪氨酸的基序，并可能需要形成L-Tetherin同源二聚体，因为S-Tetherin共表达会削弱较长异构体激活NF-κB的能力。这些结果表明了一种新的机制来控制Tetherin的抗病毒和信号功能，并为深入了解Tetherin在感染和未感染时的功能提供了依据。对先天免疫的调节对于在控制感知到的威胁和免疫病理学之间保持平衡至关重要。干扰素诱导的细胞因子Tetherin已被证明可以限制包括人类免疫缺陷病毒在内的广泛包膜病毒的萌发。尽管Tetherin似乎是一种真正的病毒限制因子，但还观察到了其他细胞功能，包括参与极化细胞中肌动蛋白的细胞骨架组织，调节干扰素的分泌，并通过核因子-kappaB(NF-κB)传递信号。我们的研究提出了一种机制，通过产生交替翻译的异构体，在翻译水平上调节Tetherin功能。观察到Tetherin的短异构体对HIV-1 VPU的抵抗力明显更强。相反，较长的异构体可以诱导NF-κB活性，这是短异构体所缺乏的功能。关键的NF-κB信号残基包括一个双酪氨酸基序，它只存在于长亚型中。对这些异构体的鉴定有助于阐明Tetherin是如何发挥作用的，不仅是一个限制因子，而且是一个信号分子。这些数据突显了以前不为人知的监管水平，并加深了我们对Tetherin额外功能的理解。
Tetherin (BST-2/CD317/HM1.24) is an IFN induced transmembrane protein that restricts release of a broad range of enveloped viruses. Important features required for Tetherin activity and regulation reside within the cytoplasmic domain. Here we demonstrate that two isoforms, derived by alternative translation initiation from highly conserved methionine residues in the cytoplasmic domain, are produced in both cultured human cell lines and primary cells. These two isoforms have distinct biological properties. The short isoform (s-Tetherin), which lacks 12 residues present in the long isoform (l-Tetherin), is significantly more resistant to HIV-1 Vpu-mediated downregulation and consequently more effectively restricts HIV-1 viral budding in the presence of Vpu. s-Tetherin Vpu resistance can be accounted for by the loss of serine-threonine and tyrosine motifs present in the long isoform. By contrast, the l-Tetherin isoform was found to be an activator of nuclear factor-kappa B (NF-κB) signaling whereas s-Tetherin does not activate NF-κB. Activation of NF-κB requires a tyrosine-based motif found within the cytoplasmic tail of the longer species and may entail formation of l-Tetherin homodimers since co-expression of s-Tetherin impairs the ability of the longer isoform to activate NF-κB. These results demonstrate a novel mechanism for control of Tetherin antiviral and signaling function and provide insight into Tetherin function both in the presence and absence of infection. Regulation of innate immunity is critical to maintain a balance between control of a perceived threat and immunopathology. The interferon induced cellular factor Tetherin has been shown to restrict budding of a broad range of enveloped viruses including the human immunodeficiency virus. Though Tetherin appears to be a bona fide viral restriction factor, additional cellular functions have been observed including an involvement in actin cytoskeleton organization in polarized cells, regulating interferon secretion and signaling through nuclear factor-kappa B (NF-κB). Our studies present a mechanism by which Tetherin function is regulated at the translational level through the production of alternatively translated isoforms. The short isoform of Tetherin was observed to be significantly more resistant to HIV-1 Vpu. In contrast, the longer isoform can induce NF-κB activity, a function lacking in the short isoform. Critical NF-κB signaling residues include a dual tyrosine motif, which is only present in the long isoform. Identification of these isoforms helps to illuminate how Tetherin functions, not only as a restriction factor, but also as a signaling molecule. These data highlight a previously unappreciated level of regulation and furthers our understanding of additional Tetherin functions.
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