The adhesion GPCR ADGRL2 engages Gα13 to enable epidermal differentiation
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Xue Yang
Feng He
Institute of Environmental Processes and Pollution Control, School of Environment and Ecology
Vanessa Lopez-Pajares
Douglas F. Porter
Krassimira Garbett
Department of Pharmacology, Vanderbilt Brain Institute, Vanderbilt University
Zurab Siprashvili
Program in Epithelial Biology, Stanford University School of Medicine
Luca Ducoli
Robin M. Meyers
David L. Reynolds
Program in Epithelial Biology, Stanford University School of Medicine
Duy Lan Huong Bui
Department of Pharmacology, Vanderbilt Brain Institute, Vanderbilt University
Audrey Hong
Program in Epithelial Biology, Stanford University School of Medicine
Duy Thanh Nguyen
Program in Epithelial Biology, Stanford University School of Medicine
Yuqing Jing
Department of Genetics, Stanford University School of Medicine
Smarajit Mondal
Program in Epithelial Biology, Stanford University School of Medicine
Lisa Ko
Program in Epithelial Biology, Stanford University School of Medicine
Shiying Tao
Program in Epithelial Biology, Stanford University School of Medicine
Bharti Singal
Department of Molecular and Cellular Physiology, Stanford University School of Medicine
Richard Sando
Department of Pharmacology, Vanderbilt Brain Institute, Vanderbilt University
Georgios Skiniotis
Paul A. Khavari