Abstract
Low-density lipoprotein receptor (LDLR) in hepatocytes plays a key role in plasma clearance of circulating LDL and in whole body cholesterol homeostasis. The trafficking of LDLR is highly regulated in clathrin-dependent endocytosis, endosomal recycling and lysosomal degradation. Current studies focus on its endocytosis and degradation. However, the detailed molecular and cellular mechanisms underlying its endosomal recycling are largely unknown. We found that BLOS1, a shared subunit of BLOC-1 and BORC, is involved in LDLR endosomal recycling. Loss of BLOS1 leads to less membrane LDLR and impairs LDL clearance from plasma in hepatocyte-specific BLOS1 knockout mice. BLOS1 interacts with kinesin-3 motor KIF13A, and BLOS1 acts as a new adaptor for kinesin-2 motor KIF3 to coordinate kinesin-3 and kinesin-2 during the long-range transport of recycling endosomes (REs) to plasma membrane along microtubule tracks to overcome hurdles at microtubule intersections. This provides new insights into RE's anterograde transport and the pathogenesis of dyslipidemia.
Highlights
Low-density lipoprotein receptor (LDLR) is essential for cellular uptake of cholesterol-carrying low-density lipoproteins (LDL) and plays a crucial role in cholesterol homeostasis in mammals (Goldstein & Brown, 2009, 2015)
To investigate whether BLOS1 deficiency could affect liver lipid droplet content, we performed Oil Red O staining on frozen sections of mouse livers and found that cKO mice had fewer lipid droplets in the liver when fed on chow diet, and the accumulation of lipid droplets after starvation was largely inhibited in cKO mouse liver (Fig. 1c-e)
Mass spectrometry identified this protein as apolipoprotein E (ApoE) (Fig. S1c), and immunoblotting confirmed the increase of ApoE in cKO mice plasma (Fig. 1g)
Summary
Low-density lipoprotein receptor (LDLR) is essential for cellular uptake of cholesterol-carrying low-density lipoproteins (LDL) and plays a crucial role in cholesterol homeostasis in mammals (Goldstein & Brown, 2009, 2015). In the slow recycling pathway, receptors are first sorted into the perinuclear endocytic recycling compartment (ERC) and transported to the cell periphery by recycling endosomes (REs) (Naslavsky & Caplan, 2018; Yamashiro, Tycko, Fluss, & Maxfield, 1984). KIF16B, another member of kinesin-3, functions in regulating the motility of early endosomes and degradation of EGF receptor, and in the transcytosis of TfR in polarized epithelial cells (Hoepfner et al, 2005; Perez Bay et al, 2013). A kinesin-2 member KIF3B has been implicated in the recycling of TfR through the interaction with RAB11-FIP5 (Schonteich et al, 2008). Whether and how these different kinesins coordinate in the transport of REs are largely unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
