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

Bare, Yonis; Chan, Grace K.; Hayday, Thomas; McGrath, John A.; Parsons, Maddy

doi:10.1016/j.jid.2020.08.011

Cited by 10 publications

(7 citation statements)

References 31 publications

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“…(3) Exophlin-5/Slac-b Genetic mutation of exophilin-5 causes an autosomal recessive form of epidermolysis bullosa simplex that results in skin fragility and erosions (McGrath et al, 2012). Although the molecular pathogenesis is largely unknown, exophilin-5-deficient keratinocytes exhibit defects in cell adhesion and reduced secretion of extracellular vesicles containing extracellular matrix proteins (Bare et al, 2020), consistent with the reported role of exophilin-5 in exosome secretion (Ostrowski et al, 2010). It has recently been shown that exophlin-5 knockout mice exhibit increased allergic airway inflammation (Okunishi et al, 2020).…”

Section: The Structure and Function Of Rab27 Effectorsmentioning

confidence: 99%

In vivo Roles of Rab27 and Its Effectors in Exocytosis

Izumi

2021

Cell Struct. Funct.

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The monomeric GTPase Rab27 regulates exocytosis of a broad range of vesicles in multicellular organisms. Several effectors bind GTP-bound Rab27a and/or Rab27b on secretory vesicles to execute a series of exocytic steps, such as vesicle maturation, movement along microtubules, anchoring within the peripheral F-actin network, and tethering to the plasma membrane, via interactions with specific proteins and membrane lipids in a local milieu. Although Rab27 effectors generally promote exocytosis, they can also temporarily restrict it when they are involved in the rate-limiting step. Genetic alterations in Rab27-related molecules cause discrete diseases manifesting pigment dilution and immunodeficiency, and can also affect common diseases such as diabetes and cancer in complex ways. Although the function and mechanism of action of these 2 effectors have been explored, it is unclear how multiple effectors act in coordination within a cell to regulate the secretory process as a whole. It seems that Rab27 and various effectors constitutively reside on individual vesicles to perform consecutive exocytic steps. The present review describes the unique properties and in vivo roles of the Rab27 system, and the functional relationship among different effectors coexpressed in single cells, with pancreatic beta cells used as an example.

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Section: The Structure and Function Of Rab27 Effectorsmentioning

confidence: 99%

In vivo Roles of Rab27 and Its Effectors in Exocytosis

Izumi

2021

Cell Struct. Funct.

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“…Keratinocytes expressing mutant Slac2‐b or with Slac2‐b knocked out showed reduced release of exosome vesicles containing extracellular matrix. Additionally, CD63 + vesicles, which were correlated with focal adhesion dynamics, were mislocalized in Slac‐2b‐depleted cells 10 . Taken together, it is plausible that Slac‐2b contributes to epidermal integrity through focal adhesions, which might explain the milder form of blistering in EB patients with EXPH5 mutations.…”

Section: Discussionmentioning

confidence: 92%

Potential di‐genic contribution to guttate leukoderma as the predominant feature of epidermolysis bullosa simplex

Koren

Zagairy

Tatour

et al. 2022

Experimental Dermatology

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Inherited epidermolysis bullosa (EB) simplex is a heterogeneous group of skin fragility disorders caused by mutations in genes encoding cell‐cell or cell‐matrix adhesion proteins. A recently identified, rare subtype of EB simplex is due to bi‐allelic mutations in the EXPH5 gene, which encodes exophilin5, an effector protein of the Rab27B GTPase involved in intracellular vesicle trafficking and exosome secretion. The EXPH5 EB subtype is characterized by early‐onset skin blisters and scars, mainly on extremities, and varying degrees of pigmentary alterations. Here, we present a 31‐year‐old female with diffuse guttate hypopigmentation on the trunk and extremities since early childhood, with no apparent blisters or scars. We employed whole exome sequencing of germline DNA extracted from the patient's leukocytes to determine the genetic aetiology of the phenotype. A novel homozygous variant in EXPH5, c.1153C>T causing a premature stop codon at amino acid Glutamine 385, was identified. Histologic examination after skin pricking disclosed focal keratinocyte detachment typical to EB. Additionally, we identified a deleterious‐predicted variant in ENPP1, a gene associated with disturbed transfer of melanosomes to keratinocytes in Cole disease. Our report expands the clinical spectrum of inherited EB simplex with a possible di‐genic synergism contributing to co‐presentation with guttate leukoderma.

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“…Although these genes lack previous reports of direct association with NSOFCs phenotypes, they have been implicated in processes crucial for craniofacial development. The EXPH5 gene, for instance, has been shown to play a role in cell-cell adhesion 32 ; a critical process in craniofacial morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

Rare Variants Analyses Suggest Novel Cleft Genes in the African Population

Alade,

Mossey,

Awotoye

et al. 2024

Preprint

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Non-syndromic orofacial clefts (NSOFCs) are common birth defects with a complex etiology. While over 60 common risk loci have been identified, they explain only a small proportion of the heritability for NSOFC. Rare variants have been implicated in the missing heritability. Thus, our study aimed to identify genes enriched with nonsynonymous rare coding variants associated with NSOFCs. Our sample included 814 non-syndromic cleft lip with or without palate (NSCL/P), 205 non-syndromic cleft palate only (NSCPO), and 2150 unrelated control children from Nigeria, Ghana, and Ethiopia. We conducted a gene-based analysis separately for each phenotype using three rare-variants collapsing models: (1) protein-altering (PA), (2) missense variants only (MO); and (3) loss of function variants only (LOFO). Subsequently, we utilized relevant transcriptomics data to evaluate associated gene expression and examined their mutation constraint using the gnomeAD database. In total, 13 genes showed suggestive associations (p = E-04). Among them, eight genes (ABCB1, ALKBH8, CENPF, CSAD, EXPH5, PDZD8, SLC16A9, and TTC28) were consistently expressed in relevant mouse and human craniofacial tissues during the formation of the face, and three genes (ABCB1, TTC28, and PDZD8) showed statistically significant mutation constraint. These findings underscore the role of rare variants in identifying candidate genes for NSOFCs. Main documents (excluding the methods section) word count: 2145

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

Cited by 10 publications

References 31 publications

In vivo Roles of Rab27 and Its Effectors in Exocytosis

In vivo Roles of Rab27 and Its Effectors in Exocytosis

Potential di‐genic contribution to guttate leukoderma as the predominant feature of epidermolysis bullosa simplex

Rare Variants Analyses Suggest Novel Cleft Genes in the African Population

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