Work

Ciliary regulation of melanogenesis unveils moonlighting roles for Joubert Syndrome proteins

Year: 2026

Type: preprint

Abstract: We previously found that skin tone correlates with intronic polymorphisms influencing the expression of the Joubert Syndrome (JS) ciliopathy gene TMEM138 , suggesting that primary cilia might regulate pigment production in skin melanocytes. Herein, we show that many ciliary proteins regulate basal pigmentation in wild-type mouse and human melanocytes by facilitating primary cilium-dependent Melanocortin-1 receptor signaling, and downstream activation of the Microphthalmia transcription factor and melanogenic gene expression. Additionally, we identify an extra-ciliary moonlighting role for TMEM138 and other JS proteins in endolysosomal organization required for the biogenesis of melanosomes, the pigment-producing lysosome-related organelle in melanocytes. Our results provide new mechanistic insights into the physiological regulation of pigmentation and suggest that JS-specific pathology might be mediated by ciliary-independent mechanisms.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.09.27.754807

Authors: Brice Magne, Sara Forsey, Dawn C. Harper, Jiyu Zhang, Chloe E. Snider, Yuanqing Feng, Sarah A. Tishkoff, Alanna Strong, Theodore G. Drivas, Colin R. Goding, Robert J. Lee, Michael S. Marks

Institutions: Children's Hospital of Philadelphia, University of Pennsylvania, University of Oxford, Ludwig Cancer Research

Language: English

Topic: melanin and skin pigmentation

Subfield: Cell Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: National Eye Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases

Awards: Genetic and molecular basis for variation in human skin pigmentation, Hermansky-Pudlak syndrome and melanosome formation, Penn Skin Biology and Diseases Resource-based Center

OpenAlex ID: W7214649209

Cites: 87

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Related to: 10