Slac2-b Coordinates Extracellular Vesicle Secretion to Regulate Keratinocyte Adhesion and Migration

TY - JOUR

T1 - Slac2-b Coordinates Extracellular Vesicle Secretion to Regulate Keratinocyte Adhesion and Migration

AU - Bare, Yonis

AU - Chan, Grace K.

AU - Hayday, Thomas

AU - McGrath, John A.

AU - Parsons, Maddy

N1 - Publisher Copyright: © 2021 The Authors

PY - 2024/9/30

Y1 - 2024/9/30

N2 - Slac2-b, also known as exophilin-5, is a Rab27b effector protein with a role in exosome transport and is encoded by the EXPH5 gene. We previously described biallelic loss-of-function mutations in EXPH5 in an autosomal recessive form of epidermolysis bullosa simplex. However, how the loss of Slac2-b expression leads to skin fragility and erosions is unknown. In this study, we demonstrate that keratinocytes (KCs) isolated from two different individuals with mutations in EXPH5 have significant defects in cell‒matrix adhesion. EXPH5-mutant KCs also showed increased perinuclear accumulation and significantly reduced trafficking of CD63+ vesicles. These phenotypes were also seen in Slac2-b‒deficient KCs. This was coincident with a reduction in Rab27a protein expression in Slac2-b‒mutant KCs as well as reduced secretion of extracellular vesicles containing extracellular matrix proteins. Live imaging analysis revealed a strong correlation between CD63+ vesicle trafficking to the plasma membrane and focal adhesion dynamics. These findings support a role for Slac2-b in regulating local focal adhesion dynamics to support effective KC adhesion and provide insight into the underlying pathophysiology of inherited skin blistering.

AB - Slac2-b, also known as exophilin-5, is a Rab27b effector protein with a role in exosome transport and is encoded by the EXPH5 gene. We previously described biallelic loss-of-function mutations in EXPH5 in an autosomal recessive form of epidermolysis bullosa simplex. However, how the loss of Slac2-b expression leads to skin fragility and erosions is unknown. In this study, we demonstrate that keratinocytes (KCs) isolated from two different individuals with mutations in EXPH5 have significant defects in cell‒matrix adhesion. EXPH5-mutant KCs also showed increased perinuclear accumulation and significantly reduced trafficking of CD63+ vesicles. These phenotypes were also seen in Slac2-b‒deficient KCs. This was coincident with a reduction in Rab27a protein expression in Slac2-b‒mutant KCs as well as reduced secretion of extracellular vesicles containing extracellular matrix proteins. Live imaging analysis revealed a strong correlation between CD63+ vesicle trafficking to the plasma membrane and focal adhesion dynamics. These findings support a role for Slac2-b in regulating local focal adhesion dynamics to support effective KC adhesion and provide insight into the underlying pathophysiology of inherited skin blistering.

UR - http://www.scopus.com/inward/record.url?scp=85091502340&partnerID=8YFLogxK

U2 - 10.1016/j.jid.2020.08.011

DO - 10.1016/j.jid.2020.08.011

M3 - Article

C2 - 32890627

AN - SCOPUS:85091502340

SN - 0022-202X

VL - 141

SP - 523-532.e2

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 3

ER -