2026年9月9日，美国迈阿密大学米勒医学院Daniel G. Isom等科学家在《自然》（Nature）发表研究，揭示了TM184C作为GPCR样调控因子在细胞间连接、物质交换和自噬中的作用。

序列相似性是大多数蛋白质注释的基础，但许多功能仍隐藏在可检测的同源性之外。通过挖掘数百万个AlphaFold2模型，研究人员鉴定出两个人类“超暗”七次跨膜蛋白家族——TM184和PRRT——它们在结构上与G蛋白偶联受体（GPCR）同源。这些蛋白表现出GPCR的标志性活性，包括β-arrestin募集和GPCR激酶（GRK）依赖性磷酸化。在此，研究人员聚焦于TM184C——表达最广泛且进化上最保守的超暗GPCR样蛋白，它定位于高度动态的细胞内囊泡而非质膜。这些囊泡沿微管移动，在细胞突起中积累，并促进隧道纳米管样和肿瘤微管样细胞间连接的形成。这些桥接结构通过一个需要TM184C C端尾部及其arrestin code基序的过程介导细胞器共享，将GPCR样β-arrestin和GRK调控与囊泡功能和细胞间连接联系起来。TM184C还通过限制LC3B脂化和自噬体积累来约束自噬流——这一作用高度保守，因为人类TM184C能在缺乏其同源物Hfl1的酵母中恢复自噬体稳态。总之，这些发现说明了基于结构的蛋白质发现如何照亮暗蛋白质组，并将TM184C鉴定为一种古老的GPCR样调控因子，调控自噬、细胞间连接和物质交换。

附：英文原文

Title: TM184C is a GPCR-like regulator of intercellular exchange and autophagy

Author: Lee, Kyutae D., Taylor, Samuel, Arcuri, Jennifer, Chandthakuri, Shraddha, Pujols, Jacinda, Colon, Bruno, Wang, Qiang, Wu, Chenzhou, Meng, Zhipeng, Thompson-Ceccato, Sebastian J., Mitchell, Jonathan, Bayik, Defne, Carbone, Alexandra, Slepak, Vladlen, Slepak, Tatiana I., Welford, Scott M., Ivan, Michael E., Wang, Dazhi, Goldberg, Blake O., Baringer, Warner, Maradzike, Elvis, Isom, Daniel G.

Issue&Volume: 2026-09-09

Abstract: Sequence similarity underlies most protein annotation, yet many functions remain hidden beyond detectable homology1,2,3. By mining millions of AlphaFold2 models4,5, we identify two human families of ‘superdark’ seven-transmembrane proteins—TM184 and PRRT—with structural homology to G-protein-coupled receptors (GPCRs). These proteins exhibit hallmark GPCR activities, including β-arrestin recruitment and GPCR kinase (GRK)-dependent phosphorylation. Here we focus on TM184C—the most broadly expressed and evolutionarily conserved superdark GPCR-like protein, which localizes to highly dynamic intracellular vesicles rather than the plasma membrane. These vesicles move along microtubules, accumulate in cell projections and promote the formation of tunnelling nanotube- and tumour microtubule-like intercellular connections. These bridges mediate organelle sharing through a process that requires the TM184C C-terminal tail and its arrestin code motif6, linking GPCR-like β-arrestin and GRK regulation to vesicle function and intercellular connectivity. TM184C also constrains autophagic flux by limiting LC3B lipidation and autophagosome accumulation—a role that is deeply conserved, as human TM184C restores autophagic body homeostasis in yeast lacking its homologue, Hfl1. Together, these findings illustrate how structure-based protein discovery can illuminate the dark proteome and identify TM184C as an ancient GPCR-like regulator of autophagy, intercellular connectivity and material exchange.

DOI: 10.1038/s41586-026-10993-8

Source: https://www.nature.com/articles/s41586-026-10993-8