Specificity of TGF-β1 signal designated by LRRC33 and integrin αVβ8

• Published in: Nature communications 2022-08, Vol.13 (1), p.4988-4988, Article 4988
• Main Authors: Duan, Zelin, Lin, Xuezhen, Wang, Lixia, Zhen, Qiuxin, Jiang, Yuefeng, Chen, Chuxin, Yang, Jing, Lee, Chia-Hsueh, Qin, Yan, Li, Ying, Zhao, Bo, Wang, Jianchuan, Zhang, Zhe
• Format: Article
• Language: English
• Subjects: 101/28; 13/1; 631/535/1258/1259; 631/80/79/1236; 631/80/86/2368; 82/103; 82/80; 82/83; 96/31; Avidity; Binding; Growth factors; Humanities and Social Sciences; Isoforms; Localization; Membrane proteins; Microenvironments; multidisciplinary; Science; Science (multidisciplinary); Signaling; Transforming growth factor-b1
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32655-9

Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin α V β 8 activates extracellular L-TGF-β1 to trigger the downstream signaling functions. However, the mechanism designating the specificity of TGF-β1 presentation and activation remains incompletely understood. Here, we report cryo-EM structures of human L-TGF-β1/LRRC33 and integrin α V β 8 /L-TGF-β1 complexes. Combined with biochemical and cell-based analyses, we demonstrate that LRRC33 only presents L-TGF-β1 but not the -β2 or -β3 isoforms due to difference of key residues on the growth factor domains. Moreover, we reveal a 2:2 binding mode of integrin α V β 8 and L-TGF-β1, which shows higher avidity and more efficient L-TGF-β1 activation than previously reported 1:2 binding mode. We also uncover that the disulfide-linked loop of the integrin subunit β 8 determines its exquisite affinity to L-TGF-β1. Together, our findings provide important insights into the specificity of TGF-β1 signaling achieved by LRRC33 and integrin α V β 8 . Microenvironment localization and activation of L-TGF-β1 determine its specific function. Here, the authors elucidated the underlying mechanisms of specific presentation of L-TGF-β1 on the surface of myeloid lineage cells designated by LRRC33, and its activation by integrin αVβ8.