KIF13B enhances the endocytosis of LRP1 by recruiting LRP1 to caveolae.
Multifunctional low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) recognizes and internalizes a large number of diverse ligands, including LDL and factor VIII. However, little is known about the regulation of LRP1 endocytosis. Here, we show that a microtubule-based motor protein, KIF13B, in an unexpected and unconventional function, enhances caveolin-dependent endocytosis of LRP1. KIF13B was highly expressed in the liver and was localized on the sinusoidal plasma membrane of hepatocytes. KIF13B knockout (KO) mice showed elevated levels of serum cholesterol and factor VIII, and KO MEFs showed decreased uptake of LDL. Exogenous KIF13B, initially localized on the plasma membrane with caveolae, was translocated to the vesicles in the cytoplasm with LRP1 and caveolin-1. KIF13B bound to hDLG1 and utrophin, which, in turn, bound to LRP1 and caveolae, respectively. These linkages were required for the KIF13B-enhanced endocytosis of LRP1. Thus, we propose that KIF13B, working as a scaffold, recruits LRP1 to caveolae via LRP1-hDLG1-KIF13B-utrophin-caveolae linkage and enhances the endocytosis of LRP1.
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Yoshimitsu
Y
Kanai
Daliang
D
Wang
Nobutaka
N
Hirokawa
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D021941:Caveolae / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D000074288:Discs Large Homolog 1 Protein; D004705:Endocytosis; D049452:Green Fluorescent Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D016547:Kinesins / Q000737:chemistry / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D022161:Transport Vesicles / Q000378:metabolism; D049411:Utrophin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008077:Lipoproteins, LDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008565:Membrane Proteins; D049411:Utrophin; D049452:Green Fluorescent Proteins; C587627:KIF13b protein, mouse; D016547:Kinesins