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Studies on the molecular mechanisms of skin pigmentation

Marubashi Sojiro 東北大学

2020.03.25

概要

Melanosomes are specialized organelles where melanin pigment is synthesized by melanogenic enzymes in mammalian skin melanocytes. Mature darkly pigmented melanosomes are transported to the periphery of the melanocytes along the cytoskeleton, and they are ultimately transferred to surrounding keratinocytes through the melanocyte dendrites, specialized cell structures that can contact surrounding keratinocytes. During the past few decades, a number of proteins involved in the biogenesis and transport of melanosomes and their functions in melanocytes have gradually been elucidated, but the regulatory mechanism of those proteins are poorly understood. Moreover, the proteins that are related to subsequent processes such as accumulation and decomposition of the incorporated melanosomes in keratinocytes are poorly identified. In this thesis, I report two mechanisms involving mammalian skin pigmentation: “RACK1 regulates dendrite outgrowth in melanocytes (Chapter 1)” and “Rab7B/42 promotes protein degradation on melanosomes in keratinocytes (Chapter 2)”.

In Chapter 1, I focused on the regulatory mechanism of Varp (VPS9-ankyrin repeat protein) protein expression. Previous studies from our groups have shown that Varp is a pleiotropic regulator of melanogenesis; it promotes dendrite formation as well as melanogenic enzyme transport to melanosomes. Furthermore, the Varp protein level has been shown to be negatively regulated by proteasomal degradation through interaction with the small GTPase Rab40C. However, the molecular mechanisms by which Varp escapes from Rab40C and retains its own expression level remain completely unknown. In this chapter, I screened for a Varp binding protein and succeeded in identifying RACK1 (receptor of activated protein kinase C 1) as a novel Varp binding partner. I found that knockdown of endogenous RACK1 in melanocytes caused dramatic reduction of the Varp protein level and inhibition of dendrite outgrowth. Furthermore, competitive co-immunoprecipitation assay showed that RACK1 inhibits the interaction between Varp and Rab40C. These findings indicated that RACK1 competes with Rab40C for binding to Varp and regulates dendrite outgrowth through stabilization of Varp in melanocytes.

In Chapter 2, I focused on the molecular basis of melanosome uptake and decomposition in keratinocytes. Although several proteins such as LAMP1 (lysosomal-associated membrane protein 1) have been observed in melanosome-containing compartments in keratinocytes, no specific marker protein for such compartments has been identified, and no appropriate assay to assess the degradation of proteins on melanosomes in keratinocytes has been established. In the second chapter, I performed a comprehensive localization screening for mammalian Rab family small GTPases (Rab1~45) and succeeded in identifying 11 Rabs that were enriched around melanosomes that had been incorporated into keratinocytes. I also developed a new assay to quantitatively assess the degradation of proteins on such melanosomes in keratinocytes and found that depletion of Rab7B (also identified as Rab42) in keratinocytes resulted in the strongest inhibition of protein degradation on incorporated melanosomes. These results indicated that Rab7B/42 is recruited to melanosome-containing compartments and that it promotes protein degradation on melanosomes in keratinocytes.

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