The GTPase-deficient Rab27A(Q78L) Mutant Inhibits Melanosome Transport in Melanocytes through Trapping of Rab27A Effector Protein Slac2-a/Melanophilin in Their Cytosol

Ishida, Morié; Arai, Saki P.; Ohbayashi, Norihiko; Fukuda, Mitsunori

doi:10.1074/jbc.m114.552281

Cited by 21 publications

(15 citation statements)

References 49 publications

(52 reference statements)

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“…While wild-type EGFP-RAB27A showed a clear punctate localization on melanosomes (Figure 3, middle panels), EGFP-RAB27A (Val143Ala) was only weakly associated with melanosomes ( Figure 3, lower panels) and some portions of the mutant protein seemed to localize in the cytosol similar to EGFP alone (Figure 3, top panels). As EGFP-RAB27A (Val143Ala) had no effect on the distribution of melanosomes, in contrast to EGFP-tagged mouse RAB27A (Gln78Leu) previously described (32), the Val143Ala mutation did not confer a dominantnegative function on RAB27A in melanosome transport. These results suggested that while the RAB27A (Val143Ala) mutant partially impaired localization, it did not produce a dominantnegative phenotype when over-expressed in melanocytes.…”

Section: Subcellular Localization and Function Of Rab27a(val143ala) Icontrasting

confidence: 59%

Griscelli Syndrome Type 2 Sine Albinism: Unraveling Differential RAB27A Effector Engagement

et al. 2020

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Griscelli syndrome type 2 (GS-2) is an inborn error of immunity characterized by partial albinism and episodes of hemophagocytic lymphohistiocytosis (HLH). It is caused by RAB27A mutations that encode RAB27A, a member of the Rab GTPase family. RAB27A is expressed in many tissues and regulates vesicular transport and organelle dynamics. Occasionally, GS-2 patients with RAB27A mutation display normal pigmentation. The study of such variants provides the opportunity to map distinct binding sites for tissue-specific effectors on RAB27A. Here we present a new case of GS-2 without albinism (GS-2 sine albinism) caused by a novel missense mutation (Val143Ala) in the RAB27A and characterize its functional cellular consequences. Using pertinent animal cell lines, the Val143Ala mutation impairs both the RAB27A–SLP2-A interaction and RAB27A–MUNC13-4 interaction, but it does not affect the RAB27A–melanophilin (MLPH)/SLAC2-A interaction that is crucial for skin and hair pigmentation. We conclude that disruption of the RAB27A–MUNC13-4 interaction in cytotoxic lymphocytes leads to the HLH predisposition of the GS-2 patient with the Val143Ala mutation. Finally, we include a review of GS-2 sine albinism cases reported in the literature, summarizing their genetic and clinical characteristics.

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Section: Subcellular Localization and Function Of Rab27a(val143ala) Icontrasting

confidence: 59%

Griscelli Syndrome Type 2 Sine Albinism: Unraveling Differential RAB27A Effector Engagement

et al. 2020

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“…Previous studies have shown that Rab27a regulates melanosome transport in melanocytes. Dysfunction in this process has been proposed to cause type 2 Griscelli syndrome, a disease characterized by silvery hair 18 , which was also confirmed by our experiment (Fig. 5a ), The Rab27a KO mouse had gray coat color compared to wild-type mouse.…”

Section: Resultssupporting

confidence: 86%

The harsh microenvironment in infarcted heart accelerates transplanted bone marrow mesenchymal stem cells injury: the role of injured cardiomyocytes-derived exosomes

Guo

Huang

et al. 2018

Cell Death Dis

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Stem cell therapy can be used to repair and regenerate damaged hearts tissue; nevertheless, the low survival rate of transplanted cells limits their therapeutic efficacy. Recently, it has been proposed that exosomes regulate multiple cellular processes by mediating cell survival and communication among cells. The following study investigates whether injured cardiomyocytes-derived exosomes (cardiac exosomes) affect the survival of transplanted bone marrow mesenchymal stem cells (BMSCs) in infarcted heart. To mimic the harsh microenvironment in infarcted heart that the cardiomyocytes or transplanted BMSCs encounter in vivo, cardiomyocytes conditioned medium and cardiac exosomes collected from H2O2-treated cardiomyocytes culture medium were cultured with BMSCs under oxidative stress in vitro. Cardiomyocytes conditioned medium and cardiac exosomes significantly accelerated the injury of BMSCs induced by H2O2; increased cleaved caspase-3/caspase-3 and apoptotic percentage, and decreased the ratio of Bcl-2/Bax and cell viability in those cells. Next, we explored the role of cardiac exosomes in the survival of transplanted BMSCs in vivo by constructing a Rab27a knockout (KO) mice model by a transcription activator-like effector nuclease (TALEN) genome-editing technique; Rab27a is a family of GTPases, which has critical role in secretion of exosomes. Male mouse GFP-modified BMSCs were implanted into the viable myocardium bordering the infarction in Rab27a KO and wild-type female mice. The obtained results showed that the transplanted BMSCs survival in infarcted heart was increased in Rab27a KO mice by the higher level of Y-chromosome Sry DNA, GFP mRNA, and the GFP fluorescence signal intensity. To sum up, these findings revealed that the injured cardiomyocytes-derived exosomes accelerate transplanted BMSCs injury in infarcted heart, thus highlighting a new mechanism underlying the survival of transplanted cells after myocardial infarction.

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“…Firstly, Kinesin superfamily protein 5b (KIF5b) is contributed to the outward transport of melanosome along microtubules (Noguchi et al, 2014). While melanosomes transfer from microtubules to actin filaments, melanosomes are transported by the tripartite complex consisting of Rab27a-Mlph-myosin Va and then anchored to the plasma membrane by the Rab27a-Slp2-a complex (Ohbayashi and Fukuda, 2012;Ishida et al, 2014;Fukuda, 2021). In addition, Cdc42 contributes to dendrite extension and filopodia formation (Lv et al, 2020b).…”

Section: Kl001 Inhibited Melanosome Distribution By Reducing Myosin V...mentioning

confidence: 99%

Cryptochrome 1 activation inhibits melanogenesis and melanosome transport through negative regulation of cAMP/PKA/CREB signaling pathway

et al. 2023

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Cutaneous pigmentation was recently shown to be an event regulated by clock proteins. Cryptochrome (CRY) is a key protein composing the feedback loop of circadian clock, however, the function of CRY in melanocytes remains unclear. Here, we found that KL001, a synthetic small molecule modulator of CRY1, inhibited melanin synthesis, as well as reduced melanocyte dendrite elongation and melanosome transport. In addition, the dominant role of CRY1 in KL001-induced anti-melanogenesis was revealed by small interfering RNA transfection. Cellular tyrosinase activity and expression level of melanogenic proteins, including tyrosinase, TRP-1, TRP-2, and transport proteins like Rab27a, Cdc42 and Myosin Va induced by α-MSH were remarkably reversed after KL001 treatment. Mechanistically, CRY1 activation inhibited melanogenesis through CREB-dependent downregulation of MITF and CREB phosphorylation was mediated by classical cAMP/PKA pathway. In addition, the other CRY1 activator, KL044 also suppressed cAMP/PKA/CREB pathway and inhibited melanogenesis. Finally, anti-melanogenic efficacy of KL001 was confirmed by determination of melanin contents in UVB-tanning model of brown guinea pigs, which indicated that targeting CRY1 activity, via topical application of small molecule activator, can be utilized therapeutically to manage human pigmentary disorders.

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The GTPase-deficient Rab27A(Q78L) Mutant Inhibits Melanosome Transport in Melanocytes through Trapping of Rab27A Effector Protein Slac2-a/Melanophilin in Their Cytosol

Cited by 21 publications

References 49 publications

Griscelli Syndrome Type 2 Sine Albinism: Unraveling Differential RAB27A Effector Engagement

Griscelli Syndrome Type 2 Sine Albinism: Unraveling Differential RAB27A Effector Engagement

The harsh microenvironment in infarcted heart accelerates transplanted bone marrow mesenchymal stem cells injury: the role of injured cardiomyocytes-derived exosomes

Cryptochrome 1 activation inhibits melanogenesis and melanosome transport through negative regulation of cAMP/PKA/CREB signaling pathway

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