PIKfyve regulates melanosome biogenesis

Abstract

PIKfyve, VAC14, and FIG4 form a complex that catalyzes the production of PI(3,5)P2, a signaling lipid implicated in process ranging from lysosome maturation to neurodegeneration. While previous studies have identified VAC14 and FIG4 mutations that lead to both neurodegeneration and coat color defects, how PIKfyve regulates melanogenesis is unknown. In this study, we sought to better understand the role of PIKfyve in melanosome biogenesis. Melanocyte-specific PIKfyve knockout mice exhibit greying of the mouse coat and the accumulation of single membrane vesicle structures in melanocytes resembling multivesicular endosomes. PIKfyve inhibition blocks melanosome maturation, the processing of the melanosome protein PMEL, and the trafficking of the melanosome protein TYRP1. Taken together, these studies identify a novel role for PIKfyve in controlling the delivery of proteins from the endosomal compartment to the melanosome, a role that is distinct from the role of PIKfyve in the reformation of lysosomes from endolysosomes.

PIKfyve complex regulates early melanosome homeostasis required for physiological amyloid formation

“…It is possible that long-term inhibition of PIKfyve activity may damage melanosome integrity by triggering an accumulation of toxic PMEL aggregates and/or melanin intermediates, perhaps leading to melanocyte death. Interestingly, mice with a specific knockout for PIKfyve in pigment cells (Liggins et al, 2018) exhibit hair graying that is similar to what is seen in mouse models with impaired PMEL fibril formation (Rochin et al, 2013), and their melanocytes display vacuolar compartments that are reminiscent of our observations. Lower melanocyte survival rates may also explain why VAC14 and FIG4 mutant mice show hypopigmentation phenotypes, while we did not observe impaired pigment synthesis.…”

Chemical and biochemical control of skin pigmentation with special emphasis on mixed melanogenesis

“…The phosphoinositide 5‐kinase complex, which is composed of phosphoinositide kinase, FYVE‐type zinc finger containing phosphoinositide kinase (PIKfyve), FIG4, and VAC14, synthesizes PI(3,5)P 2 from PI(3)P (Hasegawa et al., 2017). PIKfyve is involved in the fusion of stage 1 melanosomes and lysosomes, and is important for the trafficking of melanosomal cargo and premelanosome protein (PMEL) processing (Bissig et al., 2019; Liggins et al., 2018). Thus, PI(3,5)P 2 is important for the normal development of the melanosome which affects the final pH set point.…”

Delineating the role of MITF isoforms in pigmentation and tissue homeostasis

“…To identify which Mitf isoforms are expressed in melanocytes, we first crossed Tyr::Cre ERT2 mice (Bosenberg et al, 2006) with ROSA mTmG mice (Muzumdar, Tasic, Miyamichi, Li, & Luo, 2007). In Tyr::Cre ERT2 , ROSA mTmG double heterozygous mice, injection of tamoxifen induces melanocytes to express EGFP, whereas all other cells in the epidermis express tdTomato ( Figure S1a) (Liggins et al, 2018). Single-cell suspensions were generated from mouse skin of the indicated genotypes and sorted into tdTomato+ and EGFP+ populations for bulk RNA-seq.…”