In Mitosis You Are Not: The NIMA Family of Kinases in Aspergillus, Yeast, and Mammals

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.

show abstract

Section: Introductionmentioning

confidence: 66%

Conserved NIMA kinases regulate multiple steps of endocytic trafficking

Joseph

Naslavsky

Binti

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Several NEKs are essential to form functional cilia and flagella in mammals and other organisms, including Chlamydomonas, Trypanosoma and Tetrahymena (Mahjoub et al, 2004; Pradel et al, 2006; Wloga et al, 2006). Other NEKs are more directly implicated in mitotic cell division, with defects in NEK expression likely to contribute to aberrant chromosome segregation in cancer cells (Bachus et al, 2022; Fry et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…NEKs are located at MTOCs in many organisms, including Aspergillus, yeast and human cells (Bachus et al, 2022; Fry et al, 2017; Quarmby and Mahjoub, 2005). Of the eleven mammalian NEKs, NEK2, NEK6, NEK7 and NEK9 localise to centrosomes, playing roles in mitotic spindle assembly (Moniz et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

PlasmodiumNEK1 coordinates MTOC organisation and kinetochore attachment during rapid mitosis in male gamete formation

Zeeshan,

Rashpa,

Ferguson

et al. 2024

Preprint

View full text Add to dashboard Cite

Mitosis is an important process in the cell cycle required for cells to divide. Never in mitosis (NIMA)-like kinases (NEKs) are regulators of mitotic functions in diverse organisms.Plasmodium, the causative agent of malaria is a divergent unicellular haploid eukaryote with some unusual features in terms of its mitotic and nuclear division cycle that presumably facilitate proliferation in varied environments. For example, during the sexual stage of male gametogenesis within the mosquito host, an atypical rapid closed endomitosis is observed. Three rounds of genome replication from 1N to 8N and successive cycles of multiple spindle formation and chromosome segregation occur within eight minutes followed by karyokinesis to generate haploid gametes.Our previousPlasmodiumkinome screen identified fourNekgenes, of which two, NEK2 and NEK4, are required for meiosis. NEK1 is likely to be essential for mitosis in asexual blood stage schizogony in the vertebrate host, but its function during male gametogenesis is unknown. Here, we study NEK1 location and function, using live cell imaging, ultrastructure expansion microscopy (U-ExM) and electron microscopy, together with conditional gene knockdown and proteomic approaches. We report spatiotemporal NEK1 location in real-time, coordinated with microtubule organising centre (MTOC) dynamics during the unusual mitoses at various stages of thePlasmodiumlife cycle. Knockdown studies reveal NEK1 to be an essential component of the MTOC in male cell differentiation, associated with rapid mitosis, spindle formation and kinetochore attachment. These data suggest that Plasmodium NEK1 kinase is an important component of MTOC organisation and essential regulator of chromosome segregation during male gamete formation.

show abstract

“…Consistent with the pro-mitotic function of NIMA in A . nidulans , several mammalian NEKs regulate cell division processes including spindle assembly and centrosome separation (NEK1, NEK2, NEK5–NEK7, and NEK9) and cytokinesis (NEK1, NEK2, NEK6, and NEK7) [ 5 – 16 ]. Correspondingly, misregulation of NEKs can cause aberrant cell proliferation, and overexpression of several NEKs, including NEK6, NEK7, and NEK9, is associated with multiple cancers and cardiac hypertrophy [ 8 , 17 – 20 ].…”

Section: Introductionmentioning

confidence: 99%

Conserved NIMA kinases regulate multiple steps of endocytic trafficking

et al. 2023

View full text Add to dashboard Cite

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.

show abstract

In Mitosis You Are Not: The NIMA Family of Kinases in Aspergillus, Yeast, and Mammals

Cited by 11 publications

References 264 publications

Conserved NIMA kinases regulate multiple steps of endocytic trafficking

Conserved NIMA kinases regulate multiple steps of endocytic trafficking

PlasmodiumNEK1 coordinates MTOC organisation and kinetochore attachment during rapid mitosis in male gamete formation

Conserved NIMA kinases regulate multiple steps of endocytic trafficking

Contact Info

Product

Resources

About