The adhesion GPCR ADGRL2 engages Gα13 to enable epidermal differentiation

• 成果类型: Article
• 署名作者: Yang, Xue; He, Feng; Lopez-Pajares, Vanessa; Porter, Douglas F.; Garbett, Krassimira; Siprashvili, Zurab; Ducoli, Luca; Meyers, Robin M.; Reynolds, David L.; Bui, Duy Lan Huong; Hong, Audrey; Nguyen, Duy Thanh; Jing, Yuqing; Mondal, Smarajit; Ko, Lisa; Tao, Shiying; Singal, Bharti; Sando, Richard; Skiniotis, Georgios; Khavari, Paul A.
• 署名单位: Stanford University; Stanford Medicine; Stanford University; Stanford University; Stanford Medicine; Vanderbilt University; Stanford University; Stanford Medicine; Stanford Medicine; Stanford University; Stanford University; Stanford Medicine; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Palo Alto Health Care System; St Jude Children's Research Hospital; St Jude Children's Research Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2508436122
• 发表日期: 2025-11-25
• 页码: e2508436122
• 关键词: adhesion GPCR; epidermal differentiation; G proteins; structual biology; ADGRL2; protein-coupled receptors; Mutation; GROWTH

摘要

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 G alpha 13. Follow-up tissue knockouts verified that G alpha 13 is also required for epidermal differentiation. A cryoelectron microscopy structure in lipid nanodiscs showed that ADGRL2 engages with G alpha 13 at multiple interfaces, including via an interaction between ADGRL2 intracellular loop 3 and a G alpha 13-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-G alpha 13 axis in epidermal differentiation.