Membrane contact sites (MCSs) between endoplasmic reticulum (ER) and late endosomes/lysosomes (LE/lys) are emerging as critical hubs for diverse cellular events, and changes in their extents are linked to severe neurological diseases. While recent studies show that synaptotagmin-like mitochondrial-lipid-binding (SMP) domain-containing protein PDZD8 may mediate the ER-LE/lys MCSs, the cellular functions of PDZD8 remain largely elusive. Here we attempt to investigate lipid transfer activities of PDZD8 and the extent to which its cellular functions depend on its lipid transfer activities. In accordance with recent studies, we demonstrate that PDZD8 is a Protrudin-interacting protein and PDZD8 acts as a tether at ER-LE/lys MCSs. Further, we discover that the SMP domain of PDZD8 binds glycerophospholipids and ceramides both in vivo and in vitro, and the SMP domain can transport lipids between membranes in vitro. Functionally, PDZD8 is required for LE/lys positioning and neurite outgrowth, which is dependent on the lipid transfer activity of the SMP domain.
Summary
Length‐weight relationships were determined for three fish species [Tachysurus argentivittatus (Regan, 1905); Rhodeus spinalis Oshima, 1926; Liniparhomaloptera disparis (Lin, 1934)]. All fish sample were collected using gillnets (15 × 5 m, mesh‐size 5 mm) from Moyangjiang River, China. Samples were collected quarterly from July 2006 to August 2007. The parameter b of length‐weight relationship varied from 2.52 for Rhodeus spinalis to 3.27 forLiniparhomaloptera disparis.
Early endosomes (EEs) are central hubs for cargo sorting in vesicular trafficking. Cargoes destined for degradation retain in EEs that are eventually delivered to lysosomes, while recycled cargo destined for the plasma membrane (PM) or to the Golgi are segregated into EE buds, a specialized membrane structure transiently generated on EEs during cargo sorting. Until now, the molecular basis of the membrane expansion during the biogenesis of EE buds is completely elusive. Here, we identify a protein complex containing a Vps13 domain-containing lipid transporter SHIP164, ATPase RhoBTB3 and retromer component Vps26B, promotes the membrane expansion in the biogenesis of EE buds at Golgi-EE contacts. SHIP164 depletion specifically reduces the size and number of EE buds marked by Vps26B and actin, and results in less but enlarged EEs, which can be substantially rescued by wild type SHIP164 other than lipid transfer-defective mutants, suggesting a role of lipid transfer of SHIP164 in the process. SHIP164 and RhoBTB3 interact with enzymes for phospholipid synthesis on motile Golgi vesicles, that frequently contact EEs. Functionally, SHIP164 depletion substantially reduces the trafficking of sphingomyelin to the PM, and impairs cell growth. Together, we propose a lipid transport-dependent route from the Golgi to EEs at the contacts required for EE bud biogenesis.
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