The <scp>CEP170B‐KIF2A</scp> complex destabilizes microtubule minus ends to generate polarized microtubule network

Guan, Cuirong; Hua, Shasha; Jiang, Kai

doi:10.15252/embj.2022112953

Cited by 9 publications

(3 citation statements)

References 62 publications

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“…These additional factors were not required in our reconstitution due to the inherently asymmetric activity of KIF2A with respect to the two microtubule ends, simplifying the minimal requirements for microtubule treadmilling. In cells, KIF2A’s intrinsic minus-end preference can be enhanced by proteins that promote its minus-end accumulation ( Guan et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

The minus-end depolymerase KIF2A drives flux-like treadmilling of γTuRC-uncapped microtubules

Henkin,

Brito,

Thomas

et al. 2023

Journal of Cell Biology

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During mitosis, microtubules in the spindle turn over continuously. At spindle poles, where microtubule minus ends are concentrated, microtubule nucleation and depolymerization, the latter required for poleward microtubule flux, happen side by side. How these seemingly antagonistic processes of nucleation and depolymerization are coordinated is not understood. Here, we reconstitute this coordination in vitro combining different pole-localized activities. We find that the spindle pole–localized kinesin-13 KIF2A is a microtubule minus-end depolymerase, in contrast to its paralog MCAK. Due to its asymmetric activity, KIF2A still allows microtubule nucleation from the γ-tubulin ring complex (γTuRC), which serves as a protective cap shielding the minus end against KIF2A binding. Efficient γTuRC uncapping requires the combined action of KIF2A and a microtubule severing enzyme, leading to treadmilling of the uncapped microtubule driven by KIF2A. Together, these results provide insight into the molecular mechanisms by which a minimal protein module coordinates microtubule nucleation and depolymerization at spindle poles consistent with their role in poleward microtubule flux.

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Section: Discussionmentioning

confidence: 99%

The minus-end depolymerase KIF2A drives flux-like treadmilling of γTuRC-uncapped microtubules

Henkin,

Brito,

Thomas

et al. 2023

Journal of Cell Biology

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“…Interestingly, CEP170 has also been reported to recruit MT-depolymerizing factor KIF2A to promote cilium disassembly ( 43 ). A recent study has revealed that CEP170 has the ability to localize to the minus end of noncentrosomal microtubules in cells, and KIF2A is responsible for regulating noncentrosomal microtubules ( 44 ). Therefore, we chose to prioritize CEP170 and KIF2A in our subsequent analyses to determine whether the same mechanism applied to spermatozoa.…”

Section: Resultsmentioning

confidence: 99%

CAMSAP1 role in orchestrating structure and dynamics of manchette microtubule minus-ends impacts male fertility during spermiogenesis

Hu,

Zhang,

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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The manchette is a crucial transient structure involved in sperm development, with its composition and regulation still not fully understood. This study focused on investigating the roles of CAMSAP1 and CAMSAP2, microtubule (MT) minus-end binding proteins, in regulating manchette MTs, spermiogenesis, and male fertility. The loss of CAMSAP1, but not CAMSAP2, disrupts the well-orchestrated process of spermiogenesis, leading to abnormal manchette elongation and delayed removal, resulting in deformed sperm nuclei and tails resembling oligoasthenozoospermia symptoms. We investigated the underlying molecular mechanisms by purifying manchette assemblies and comparing them through proteomic analysis, and results showed that the absence of CAMSAP1 disrupted the proper localization of key proteins (CEP170 and KIF2A) at the manchette minus end, compromising its structural integrity and hindering MT depolymerization. These findings highlight the significance of maintaining homeostasis in manchette MT minus-ends for shaping manchette morphology during late spermiogenesis, offering insights into the molecular mechanisms underlying infertility and sperm abnormalities.

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“…KIF1c is part of the kinesin family of protein transporters ( 36 ). Kinesins have a central role in cellular membrane trafficking and are essential for the function of many polar cells, such as neurons, epithelial cells, or stem cells during organogenesis ( 36 , 37 ). Kinesins also play a key role in cell-cycle dynamics ( 36 , 38 ) and in cancer cells, where they have been associated with tumor growth and metastasis ( 39 , 40 ).…”

Section: Discussionmentioning

confidence: 99%

KIF1C and new Huntingtin-interacting protein 1 binding proteins regulate rheumatoid arthritis fibroblast-like synoviocytes’ phenotypes

Laragione,

Harris,

Gulko

2024

Front. Immunol.

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BackgroundHuntingtin-interacting protein-1 (HIP1) is a new arthritis severity gene implicated in the regulation of the invasive properties of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). These invasive properties of FLS strongly correlate with radiographic and histology damage in patients with RA and rodent models of arthritis. While HIP1 has several intracellular functions, little is known about its binding proteins, and identifying them has the potential to expand our understanding of its role in cell invasion and other disease-contributing phenotypes, and potentially identify new targets for therapy.MethodsFLS cell lines from arthritic DA (highly invasive) and from arthritis-protected congenic rats R6 (minimally invasive), which differ in an amino-acid changing HIP1 SNP, were cultured and lysed, and proteins were immunoprecipitated with an anti-HIP1 antibody. Immunoprecipitates were analyzed by mass spectrometry. Differentially detected (bound) proteins were selected for functional experiments using siRNA knockdown in human RA FLS to examine their effect in cell invasiveness, adhesion, cell migration and proliferation, and immunofluorescence microscopy.ResultsProteins detected included a few known HIP1-binding proteins and several new ones. Forty-five proteins differed in levels detected in the DA versus R6 congenic mass spectrometry analyses. Thirty-two of these proteins were knocked down and studied in vitro, with 10 inducing significant changes in RA FLS phenotypes. Specifically, knockdown of five HIP1-binding protein genes (CHMP4BL1, COPE, KIF1C, YWHAG, and YWHAH) significantly decreased FLS invasiveness. Knockdown of KIF1C also reduced RA FLS migration. The binding of four selected proteins to human HIP1 was confirmed. KIF1C colocalized with lamellipodia, and its knockdown prevented RA FLS from developing an elongated morphology with thick linearized actin fibers or forming polarized lamellipodia, all required for cell mobility and invasion. Unlike HIP1, KIF1C knockdown did not affect Rac1 signaling.ConclusionWe have identified new HIP1-binding proteins and demonstrate that 10 of them regulate key FLS phenotypes. These HIP1-binding proteins have the potential to become new therapeutic targets and help better understand the RA FLS pathogenic behavior. KIF1C knockdown recapitulated the morphologic changes previously seen in the absence of HIP1, but did not affect the same cell signaling pathway, suggesting involvement in the regulation of different processes.

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The CEP170B‐KIF2A complex destabilizes microtubule minus ends to generate polarized microtubule network

Cited by 9 publications

References 62 publications

The minus-end depolymerase KIF2A drives flux-like treadmilling of γTuRC-uncapped microtubules

The minus-end depolymerase KIF2A drives flux-like treadmilling of γTuRC-uncapped microtubules

CAMSAP1 role in orchestrating structure and dynamics of manchette microtubule minus-ends impacts male fertility during spermiogenesis

KIF1C and new Huntingtin-interacting protein 1 binding proteins regulate rheumatoid arthritis fibroblast-like synoviocytes’ phenotypes

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