Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A

Häfner, Julia; Mayr, Monika I.; Möckel, Martin M.; Mayer, Thomas

doi:10.1038/ncomms5397

Cited by 63 publications

(68 citation statements)

References 41 publications

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“…An overall change in the microtubule turnover takes place at the metaphase to anaphase transition (Zhai et al, 1995). Consistent with this, previous work found that Kif18A (Hafner et al, 2014), which acts to dampen microtubule dynamics, and the chromokinesin KID (Ohsugi et al, 2003) are regulated downstream of CDK. A change in their phosphorylation status at anaphase onset may act to dampen chromosome oscillations and reduce polar ejection forces.…”

Section: Discussionsupporting

confidence: 72%

A Regulatory Switch Alters Chromosome Motions at the Metaphase-to-Anaphase Transition

Barry

Schweizer

et al. 2016

Cell Reports

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SummaryTo achieve chromosome segregation during mitosis, sister chromatids must undergo a dramatic change in their behavior to switch from balanced oscillations at the metaphase plate to directed poleward motion during anaphase. However, the factors that alter chromosome behavior at the metaphase-to-anaphase transition remain incompletely understood. Here, we perform time-lapse imaging to analyze anaphase chromosome dynamics in human cells. Using multiple directed biochemical, genetic, and physical perturbations, our results demonstrate that differences in the global phosphorylation states between metaphase and anaphase are the major determinant of chromosome motion dynamics. Indeed, causing a mitotic phosphorylation state to persist into anaphase produces dramatic metaphase-like oscillations. These induced oscillations depend on both kinetochore-derived and polar ejection forces that oppose poleward motion. Thus, our analysis of anaphase chromosome motion reveals that dephosphorylation of multiple mitotic substrates is required to suppress metaphase chromosome oscillatory motions and achieve directed poleward motion for successful chromosome segregation.

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Section: Discussionsupporting

confidence: 72%

A Regulatory Switch Alters Chromosome Motions at the Metaphase-to-Anaphase Transition

Barry

Schweizer

et al. 2016

Cell Reports

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“…Phosphorylation of cellular motor proteins to regulate intracellular trafficking has been reported in diverse cellular processes, and one major regulation mode is the phosphorylation of the C-terminal cargo-binding domains of N-kinesins (16,(31)(32)(33). The C terminus of KIF3A (KIF3Act, amino acids 531 to 702), which has been shown to bind to cargo vesicles (34), was cloned and expressed as a GST fusion protein.…”

Section: Hsv-1 Protein Kinase Us3 Specifically Downregulates the Surfmentioning

confidence: 99%

Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression

Xiong

Rao

Kim

et al. 2015

J Virol

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Herpes simplex virus 1 (HSV-1) causes one of the most prevalent herpesviral infections in humans and is the leading etiological agent of viral encephalitis and eye infections. Our understanding of how HSV-1 interacts with the host at the cellular and organismal levels is still limited. We and others previously reported that, upon infection, HSV-1 rapidly and efficiently downregulates CD1d cell surface expression and suppresses the function of NKT cells, a group of innate T cells with critical immunoregulatory function. The viral protein kinase US3 plays a major role in this immune evasion mechanism, and its kinase activity is required for this function. In this study, we investigated the cellular substrate(s) phosphorylated by US3 and how it mediates US3 suppression of CD1d recycling. We identified the type II kinesin motor protein KIF3A as a critical kinesin factor in the cell surface expression of CD1d. Interestingly, KIF3A is phosphorylated by US3 both in vitro and in infected cells. Mass spectrometry analysis of purified KIF3A showed that it is phosphorylated predominantly at serine 687 by US3. Ablation of this phosphorylation abolished US3-mediated downregulation of CD1d expression, suggesting that phosphorylation of KIF3A is the primary mechanism of HSV-1 suppression of CD1d expression by US3 protein. Understanding of the precise mechanism of viral modulation of CD1d expression will help to develop more efficient vaccines in the future to boost host NKT cell-mediated immune responses against herpesviruses. IMPORTANCEHerpes simplex virus 1 (HSV-1) is among the most common human pathogens. Little is known regarding the exact mechanism by which this virus evades the human immune system, particularly the innate immune system. We previously reported that HSV-1 employs its protein kinase US3 to modulate the expression of the key antigen-presenting molecule CD1d to evade the antiviral function of NKT cells. Here we identified the key cellular motor protein KIF3A as a cellular substrate phosphorylated by US3, and this phosphorylation event mediates US3-induced immune evasion.

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“…Transfection of siRNA targeting human Kif18A and time-lapse microscopy was performed as previously described (Häfner et al, 2014). High-resolution analysis of mitotic spindles was performed as previously described in Mayr et al (2007).…”

Section: Methodsmentioning

confidence: 99%

Xenopus laevis Kif18A is a highly processive kinesin required for meiotic spindle integrity

et al. 2017

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The assembly and functionality of the mitotic spindle depends on the coordinated activities of microtubule-associated motor proteins of the dynein and kinesin superfamily. Our current understanding of the function of motor proteins is significantly shaped by studies using Xenopus laevis egg extract as its open structure allows complex experimental manipulations hardly feasible in other model systems. Yet, the Kinesin-8 orthologue of human Kif18A has not been described in Xenopus laevis so far. Here, we report the cloning and characterization of Xenopus laevis (Xl) Kif18A. Xenopus Kif18A is expressed during oocyte maturation and its depletion from meiotic egg extract results in severe spindle defects. These defects can be rescued by wild-type Kif18A, but not Kif18A lacking motor activity or the C-terminus. Single-molecule microscopy assays revealed that Xl_Kif18A possesses high processivity, which depends on an additional C-terminal microtubule-binding site. Human tissue culture cells depleted of endogenous Kif18A display mitotic defects, which can be rescued by wild-type, but not tail-less Xl_Kif18A. Thus, Xl_Kif18A is the functional orthologue of human Kif18A whose activity is essential for the correct function of meiotic spindles in Xenopus oocytes.

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Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A

Cited by 63 publications

References 41 publications

A Regulatory Switch Alters Chromosome Motions at the Metaphase-to-Anaphase Transition

A Regulatory Switch Alters Chromosome Motions at the Metaphase-to-Anaphase Transition

Herpes Simplex Virus 1 US3 Phosphorylates Cellular KIF3A To Downregulate CD1d Expression

Xenopus laevis Kif18A is a highly processive kinesin required for meiotic spindle integrity

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