The adhesion GPCR ADGRL2 engages Gα13 to enable epidermal differentiation

作者：Yang Xue, Feng He, Vanessa Lopez-Pajares, Douglas F. Porter, Krassimira Garbett, Zurab Siprashvili, Luca Ducoli, Robin M. Meyers, David L. Reynolds, Duy Lan Huong Bui, Audrey W. Hong, Thanh Nguyen, Yuqing Jing, Smarajit Mondal, Lisa A. Ko, Shiying Tao, Bharti Singal, Richard Sando, Georgios Skiniotis, Paul A. Khavari · 发表于：Proceedings of the National Academy of Sciences · 年份：2025 · DOI：10.1073/pnas.2508436122 · 被引用次数：3 · 研究领域：Receptor Mechanisms and Signaling、Protein Kinase Regulation and GTPase Signaling、Cellular transport and secretion

Homeostasis relies on signaling networks controlled by cell membrane receptors. Although G-protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors, their specific roles in the epidermis are not fully understood. Dual CRISPR-Flow and single cell Perturb RNA-sequencing knockout screens of all epidermal GPCRs were thus performed, uncovering an essential requirement for adhesion GPCR ADGRL2 (latrophilin 2) in epidermal differentiation. Among potential downstream guanine nucleotide-binding G proteins, ADGRL2 selectively activated Gα13. Follow-up tissue knockouts verified that Gα13 is also required for epidermal differentiation. A cryoelectron microscopy structure in lipid nanodiscs showed that ADGRL2 engages with Gα13 at multiple interfaces, including via an interaction between ADGRL2 intracellular loop 3 and a Gα13-specific QQQ glutamine triplet sequence in its GTPase domain. In situ gene mutation of this interface sequence impaired epidermal differentiation, highlighting an essential new role for an ADGRL2-Gα13 axis in epidermal differentiation.