Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation.
Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation.
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DOI：
10.7554/elife.78653
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发表时间：
2022-06-22
期刊：
影响因子：
7.7
通讯作者：
Stumpff, Jason
中科院分区：
文献类型：
--
作者：
Thompson, Alex F.;Blackburn, Patrick R.;Arons, Noah S.;Stevens, Sarah N.;Babovic-Vuksanovic, Dusica;Lian, Jane B.;Klee, Eric W.;Stumpff, Jason
染色体驱动蛋白KIF22产生有助于有丝分裂染色体聚集和排列的力。在骨骼发育异常的患者中已经发现了KIF22运动域α2螺旋的突变，我们报告了一例在KIF22尾部发现新突变的患者。我们证明致病性突变不会导致KIF22在早期有丝分裂中的功能丧失。相反，突变破坏了后期的染色体分离，导致增殖减少，子细胞核形态异常，并且在一个细胞亚群中，胞质分裂失败。这种表型可以通过KIF22在后期不能表达来解释。与该模型一致，通过尾部磷酸化调节的已知位点组成性激活电机表型模仿致病突变的影响。这些结果表明，马达结构域α2螺旋可能是KIF22活性调节的重要位点，在中期到后期的过渡。为了支持这一结论，模拟α2螺旋残基T158的磷酸化也阻止了KIF22在后期的失活。这些发现证明了马达的头部和尾部在调节KIF22活性方面的重要性，并提供了对防止KIF22失活和破坏后期力平衡的细胞后果的见解。
The chromokinesin KIF22 generates forces that contribute to mitotic chromosome congression and alignment. Mutations in the α2 helix of the motor domain of KIF22 have been identified in patients with abnormal skeletal development, and we report the identification of a patient with a novel mutation in the KIF22 tail. We demonstrate that pathogenic mutations do not result in a loss of KIF22’s functions in early mitosis. Instead, mutations disrupt chromosome segregation in anaphase, resulting in reduced proliferation, abnormal daughter cell nuclear morphology, and, in a subset of cells, cytokinesis failure. This phenotype could be explained by a failure of KIF22 to inactivate in anaphase. Consistent with this model, constitutive activation of the motor via a known site of phosphoregulation in the tail phenocopied the effects of pathogenic mutations. These results suggest that the motor domain α2 helix may be an important site for regulation of KIF22 activity at the metaphase to anaphase transition. In support of this conclusion, mimicking phosphorylation of α2 helix residue T158 also prevents inactivation of KIF22 in anaphase. These findings demonstrate the importance of both the head and tail of the motor in regulating the activity of KIF22 and offer insight into the cellular consequences of preventing KIF22 inactivation and disrupting force balance in anaphase.
影响因子：
4.6
作者：
Takagi, Jun;Itabashi, Takeshi;Suzuki, Kazuya;Ishiwata, Shin'ichi
通讯作者：
Ishiwata, Shin'ichi