Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, New York 10065, United States.
Tri-Institutional Ph.D. Program in Chemical Biology, New York, New York 10065, United States.
ACS Chem Biol. 2021 May 21;16(5):844-856. doi: 10.1021/acschembio.1c00013. Epub 2021 Apr 22.
Interferon-induced transmembrane proteins (IFITMs) are -palmitoylated proteins in vertebrates that restrict a diverse range of viruses. -palmitoylated IFITM3 in particular engages incoming virus particles, prevents their cytoplasmic entry, and accelerates their lysosomal clearance by host cells. However, how -palmitoylation modulates the structure and biophysical characteristics of IFITM3 to promote its antiviral activity remains unclear. To investigate how site-specific -palmitoylation controls IFITM3 antiviral activity, we employed computational, chemical, and biophysical approaches to demonstrate that site-specific lipidation of cysteine 72 enhances the antiviral activity of IFITM3 by modulating its conformation and interaction with lipid membranes. Collectively, our results demonstrate that site-specific -palmitoylation of IFITM3 directly alters its biophysical properties and activity in cells to prevent virus infection.
干扰素诱导跨膜蛋白（IFITMs）是脊椎动物中的一种棕榈酰化蛋白，可限制多种病毒。特别是棕榈酰化的 IFITM3 可与进入的病毒颗粒结合，阻止它们进入细胞质，并通过宿主细胞加速溶酶体清除。然而，棕榈酰化如何调节 IFITM3 的结构和生物物理特性以促进其抗病毒活性仍不清楚。为了研究位点特异性棕榈酰化如何控制 IFITM3 的抗病毒活性，我们采用计算、化学和生物物理方法证明，半胱氨酸 72 位的位点特异性脂质化通过调节 IFITM3 的构象及其与脂质膜的相互作用来增强其抗病毒活性。总的来说，我们的结果表明，IFITM3 的位点特异性棕榈酰化直接改变其在细胞中的生物物理特性和活性，从而防止病毒感染。
