Liu Liqiong, Downs Micquel, Guidry Jesse, Wojcik Edward J
Department of Biochemistry and Molecular Biology, LSU School of Medicine & Health Sciences Center, New Orleans, LA 70112, USA.
The Proteomics Core Facility, LSU School of Medicine & Health Sciences Center, New Orleans, LA 70112, USA.
iScience. 2021 Mar 31;24(5):102385. doi: 10.1016/j.isci.2021.102385. eCollection 2021 May 21.
Here we identify human Kinesin-5, Kif11/HsEg5, as a cellular target of Zika protease. We show that Zika NS2B-NS3 protease targets several sites within the motor domain of HsEg5 irrespective of motor binding to microtubules. The native integral ER-membrane protease triggers mitotic spindle positioning defects and a prolonged metaphase delay in cultured cells. Our data support a model whereby loss of function of HsEg5 is mediated by Zika protease and is spatially restricted to the ER-mitotic spindle interface during mitosis. The resulting phenotype is distinct from the monopolar phenotype that typically results from uniform inhibition of HsEg5 by RNAi or drugs. In addition, our data reveal novel inter-organelle interactions between the mitotic apparatus and the surrounding reticulate ER network. Given that Kif11 is haplo-insufficient in humans, and reduced dosage results in microcephaly, we propose that Zika protease targeting of HsEg5 may be a key event in the etiology of Zika syndrome microcephaly.
在这里，我们确定人类驱动蛋白-5（Kif11/HsEg5）是寨卡病毒蛋白酶的一个细胞靶点。我们发现，寨卡病毒NS2B-NS3蛋白酶靶向HsEg5运动结构域内的多个位点，而不考虑其与微管的运动结合。这种天然的内质网整合膜蛋白酶会引发培养细胞中的有丝分裂纺锤体定位缺陷和中期延长延迟。我们的数据支持一种模型，即HsEg5功能丧失是由寨卡病毒蛋白酶介导的，并且在有丝分裂期间在空间上局限于内质网-有丝分裂纺锤体界面。由此产生的表型不同于通常由RNA干扰或药物对HsEg5的均匀抑制所导致的单极表型。此外，我们的数据揭示了有丝分裂装置与周围网状内质网网络之间新的细胞器间相互作用。鉴于Kif11在人类中具有单倍体不足性，且剂量减少会导致小头畸形，我们提出寨卡病毒蛋白酶对HsEg5的靶向作用可能是寨卡综合征小头畸形病因中的一个关键事件。
