Identification of Alternatively Translated Tetherin Isoforms with Differing Antiviral and Signaling Activities

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.Tetherin (BST-2/CD317/HM1.24) 是干扰素（IFN）诱导的跨膜蛋白，可抑制多种包膜病毒的释放。其发挥活性与调控所需的关键特征定位于胞质结构域内。本研究证实，在培养的人类细胞系及原代细胞中，可通过胞质结构域内高度保守的甲硫氨酸残基发生选择性翻译起始，产生两种同工型。这两种同工型具备截然不同的生物学特性。短型同工型（s-Tetherin）缺失长型同工型（l-Tetherin）所含的12个氨基酸残基，对HIV-1 Vpu介导的下调作用具有显著抗性，因此在Vpu存在的条件下，能更有效地阻断HIV-1病毒的出芽过程。s-Tetherin的Vpu抗性可归因于其丢失了长型同工型中存在的丝氨酸-苏氨酸及酪氨酸基序。与之相对，长型Tetherin同工型可激活核因子-κB（NF-κB）信号通路，而短型Tetherin则无该激活活性。核因子-κB的激活需要存在于该较长蛋白胞质尾区的酪氨酸基序，且可能涉及长型Tetherin同源二聚体的形成，因为共表达短型Tetherin会削弱长型同工型激活核因子-κB的能力。本研究结果揭示了一种调控Tetherin抗病毒功能与信号转导功能的全新机制，并为感染状态下及非感染状态下Tetherin的功能提供了全新的研究视角。