BLOS1 mediates kinesin switch during endosomal recycling of LDL receptor

Abstract

Low-density lipoprotein receptor (LDLR) in hepatocytes plays a key role in normal 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 have been focusing 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, and that BLOS1 acts as a new adaptor for kinesin-2 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. These findings provide new insights into RE's anterograde transport and the pathogenesis of dyslipidemia.

Alteration in Rab11‐mediated endocytic trafficking of LDL receptor contributes to angiotensin II‐induced cholesterol accumulation and injury in podocytes

“…In fact, LDLR levels on cell surfaces reflect a dynamic balance between transcriptional and post‐transcriptional processes. As a recycling receptor, internalised LDLR could be sorted towards different fates; the regulation between reuse and lysosomal degradation is central to maintaining its protein level 30,31 . Based on this, the inhibitors for proprotein convertase subtilisin/kexin 9 (PCSK9) are clinically applied to inhibit the degradation of LDLR in liver and used for cholesterol‐lowering therapies.…”

“…As a recycling receptor, internalised LDLR could be sorted towards different fates; the regulation between reuse and lysosomal degradation is central to maintaining its protein level. 30,31 Based on this, the inhibitors for proprotein convertase subtilisin/kexin 9 (PCSK9) are clinically applied to inhibit the degradation of LDLR in liver and used for cholesterol-lowering therapies. However, PCSK9 dysfunction mutations are associated with increased circulating fasting glucose concentration, body weight and an increased risk of type 2 diabetes, 32,33 suggesting that changes in LDLR levels may trigger unknown metabolic changes for peripheral cells.…”

Regulation of Blos1 by IRE1 prevents the accumulation of Huntingtin protein aggregates

“…Alternatively, as suggested by the large fraction (>50%) of untransfected cells displaying juxtanuclear RAB7 structures, Blos1 regulation may affect eMI in ways unrelated to the simple trafficking and localization of these organelles. In support of this idea, BORC, the BLOS1-containing complex responsible for LE/lysosome trafficking, has also been shown to regulate autophagosome-lysosome fusion 29 and LE/lysosome size 30 ; and BLOS1 itself also participates in a variety of related cellular functions both through its role in the biogenesis of lysosome related organelles complex (BLOC1) and potentially independently 31,32 .…”

Regulation ofBlos1by IRE1 prevents the accumulation of Huntingtin protein aggregates

“…BLOS1 is also important for several other trafficking and endosome-related functions, including the sorting of proteins in endosomal compartments ( Zhang et al. , 2014 ), kinesin switching during endosome recycling ( Zhang et al. , 2020 ), autolysosomal tubulation ( Wu et al.…”