BLOC-1 and BLOC-3 regulate VAMP7 cycling to and from melanosomes via distinct tubular transport carriers

Abstract

Dennis et al. analyze cycling of the v-SNARE VAMP7 during melanosome biogenesis in melanocytes. VAMP7 is targeted to and retrieved from maturing melanosomes in separate tubular carriers whose formation requires distinct BLOCs, each defective in variants of Hermansky–Pudlak syndrome.

Distinct features of multivesicular body‐lysosome fusion revealed by a new cell‐free content‐mixing assay

“…As with the fusion machinery, ESCRTs and potential mediators of Vps21‐Ypt7 conversion are evolutionarily conserved, suggesting the same mechanisms likely underlie MVB‐lysosome fusion in metazoan cells . Loss‐of‐function mutations in ESCRT components are linked to many human disorders, including cancers and neurodegenerative diseases .…”

Neurodevelopmental disease mechanisms, primary cilia, and endosomes converge on the BLOC‐1 and BORC complexes

“…Here we define BLOC‐1 subunit cargoes as membrane proteins that either interact with BLOC‐1 subunits, or their subcellular location and/or expression is altered by BLOC‐1 subunits mutations. The membrane proteins expressed in neurons that fulfill some or all of these BLOC‐1 cargo criteria are: diverse SNAREs (VAMP7, SNAP25, syntaxin 1A, and syntaxin 13), phosphatidyl‐inositol 4 kinase type 2 alpha (PI4K2A), the Menkes copper transporter (ATP7A), Notch1, NR2A‐containing NMDA receptors, and the dopamine D2 and D3 receptors (Numakawa et al, ; Di Pietro et al, ; Salazar et al, ; Setty et al, ; Ji et al, ; Tang et al, ; Marley and von Zastrow, ; Karlsgodt et al, ; Larimore et al, ; Dickman et al, ; Papaleo et al, ; Ryder et al, ; Saggu et al, ; Gokhale et al, ; Dennis et al, ; Schmieg et al, ; Sinclair et al, ). Of these receptors, dopamine D2 receptor is of particular interest as this neurotransmitter receptor localizes to the primary cilium, a cellular compartment whose membrane protein composition, morphology, and function are sensitive to mutations in the BLOC‐1 subunits BLOC1S6 and dysbindin/BLOC1S8 (Monis et al, ).…”

“…Downregulation of the Arp2/3 activators WASH or annexin A2 disrupt the targeting of membrane proteins destined to the late endosomes (VAMP7 and PI4K2A) or cargoes targeted to melanosomes (VAMP7 and TYRP1) demonstrating that vesicle/tubule formation events require localized activity of the Arp2/3 complex (Ryder et al, ; Delevoye et al, ; Dennis et al, ). The WASH complex and annexin A2 activate the Arp2/3 complex in endosomes yet only annexin A2 is required in melanosome biogenesis whereas the strumpellin subunit of the WASH complex is dispensable for melanosome biogenesis (Delevoye et al, ; Tyrrell et al, ).…”

“…BLOC‐1/BORC complex subunits associate with the microtubule motors dynein, kinesin 1, 3, and kinesin 13A. Dynein interacts with SNAPIN while other BORC complex subunits bridge target organelles with an Arl8b‐Kinesin‐1 or 3 complexes (Di Giovanni and Sheng, ; Pu et al, ; Delevoye et al, ; Dennis et al, ; Guardia et al, ; Farias et al, ). If the boundaries of the BLOC‐1 and BORC complex are more fluid than just two independent complexes, as suggested by the molecular interactions between BLOC‐1 and BORC subunits (see Fig.…”

Heŕmanský–Pudlák syndrome: A case report

“…The fusion of melanosomes with tubular transport carriers mediated by v-SNARE VAMP7. Illumination of SNARE recycling from melanosomes is a critical BLOC-3-dependent step which explains hypopigmentation as a clinical feature in HPS phenotype variants such as BLOC-1 and BLOC-3 deficiency [10] (Table 1).…”