title: Essential role of the molecular chaperone gp96 in regulating melanogenesis.
abstract: Through a process known as melanogenesis, melanocyte produces melanin in specialized organelles termed melanosomes, which regulates pigmentation of the skin, eyes, and hair. Gp96 is a constitutively expressed heat shock protein in the endoplasmic reticulum whose expression is further upregulated upon ultraviolet irradiation. However, the roles and mechanisms of this chaperone in pigmentation biology are unknown. In this study, we found that knockdown of gp96 by RNA interference significantly perturbed melanin synthesis and blocked late melanosome maturation. Gp96 knockdown did not impair the expression of tyrosinase, an essential enzyme in melanin synthesis, but compromised its catalytic activity and melanosome translocation. Further, mice with melanocyte-specific deletion of gp96 displayed decreased pigmentation. A mechanistic study revealed that the defect in melanogenesis can be rescued by activation of the canonical Wnt pathway, consistent with the critical roles of gp96 in chaperoning Wnt-coreceptor LRP6. Thus, this work uncovered the essential role of gp96 in regulating melanogenesis.
authors.affiliation: Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Helke
authors.forename: Sergio G
authors.initials: SG
authors.lastname: Coelho
authors.forename: Julio C
authors.initials: JC
authors.lastname: Valencia
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Hearing
authors.forename: Shaoli
authors.initials: S
authors.lastname: Sun
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology*; D008543:Melanins / Q000096:biosynthesis* / Q000235:genetics; D020460:Melanosomes / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D012880:Skin Pigmentation / Q000502:physiology*
chemical_list: D008543:Melanins; D008562:Membrane Glycoproteins; C053387:endoplasmin
keywords: Gp96; melanogenesis; melanosome; tyrosinase
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