Conserved NIMA kinases regulate multiple steps of endocytic trafficking

Human NIMA-related kinases have primarily been studied for their roles in cell cycle progression (NEK1/2/6/7/9), checkpoint-DNA-damage control (NEK1/2/4/5/10/11), and ciliogenesis (NEK1/4/8). We previously showed that Caenorhabditis elegans NEKL-2 (NEK8/9 homolog) and NEKL-3 (NEK6/7 homolog) regulat...

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Published in:	PLoS genetics Vol. 19; no. 4; p. e1010741
Main Authors:	Joseph, Braveen B, Naslavsky, Naava, Binti, Shaonil, Conquest, Sylvia, Robison, Lexi, Bai, Ge, Homer, Rafael O, Grant, Barth D, Caplan, Steve, Fay, David S
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 26-04-2023 Public Library of Science (PLoS)
Subjects:	Adapter proteins Animals Biology and Life Sciences Bone Morphogenetic Protein Receptors - metabolism Caenorhabditis elegans - metabolism Caenorhabditis elegans Proteins - genetics Caenorhabditis elegans Proteins - metabolism Cell cycle Cell division Cell lines Cell research Cell surface Cells Cellular control mechanisms Clathrin Clathrin - genetics Clathrin - metabolism DNA damage Endocytosis Endocytosis - genetics Endosomes Endosomes - genetics Endosomes - metabolism Epidermis Gene expression Genetic aspects Golgi apparatus Humans Kinases Localization Lysosomes Mannose Molting Nek1 protein NIMA-Related Kinases - genetics NIMA-Related Kinases - metabolism Physiological aspects Protein kinases Protein Transport - genetics Protein turnover Research and Analysis Methods Roles siRNA Worms United States
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Summary:	Human NIMA-related kinases have primarily been studied for their roles in cell cycle progression (NEK1/2/6/7/9), checkpoint-DNA-damage control (NEK1/2/4/5/10/11), and ciliogenesis (NEK1/4/8). We previously showed that Caenorhabditis elegans NEKL-2 (NEK8/9 homolog) and NEKL-3 (NEK6/7 homolog) regulate apical clathrin-mediated endocytosis (CME) in the worm epidermis and are essential for molting. Here we show that NEKL-2 and NEKL-3 also have distinct roles in controlling endosome function and morphology. Specifically, loss of NEKL-2 led to enlarged early endosomes with long tubular extensions but showed minimal effects on other compartments. In contrast, NEKL-3 depletion caused pronounced defects in early, late, and recycling endosomes. Consistently, NEKL-2 was strongly localized to early endosomes, whereas NEKL-3 was localized to multiple endosomal compartments. Loss of NEKLs also led to variable defects in the recycling of two resident cargoes of the trans-Golgi network (TGN), MIG-14/Wntless and TGN-38/TGN38, which were missorted to lysosomes after NEKL depletion. In addition, defects were observed in the uptake of clathrin-dependent (SMA-6/Type I BMP receptor) and independent cargoes (DAF-4/Type II BMP receptor) from the basolateral surface of epidermal cells after NEKL-2 or NEKL-3 depletion. Complementary studies in human cell lines further showed that siRNA knockdown of the NEKL-3 orthologs NEK6 and NEK7 led to missorting of the mannose 6-phosphate receptor from endosomes. Moreover, in multiple human cell types, depletion of NEK6 or NEK7 disrupted both early and recycling endosomal compartments, including the presence of excess tubulation within recycling endosomes, a defect also observed after NEKL-3 depletion in worms. Thus, NIMA family kinases carry out multiple functions during endocytosis in both worms and humans, consistent with our previous observation that human NEKL-3 orthologs can rescue molting and trafficking defects in C. elegans nekl-3 mutants. Our findings suggest that trafficking defects could underlie some of the proposed roles for NEK kinases in human disease.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1010741