A common molecular mechanism underlies the role of Mps1 in chromosome biorientation and the spindle assembly checkpoint

The conserved Mps1 kinase corrects improper kinetochore-microtubule attachments, thereby ensuring chromosome biorientation. Yet, its critical targets in this process remain elusive. Mps1 is also involved in the spindle assembly checkpoint (SAC), the surveillance mechanism halting chromosome segregation until biorientation is attained. Its role in SAC activation is antagonized by the PP1 phosphatase and involves phosphorylation of Knl1/Spc105, which recruits Bub1 to kinetochores to promote assembly of SAC effector complexes. A crucial question is whether error correction and SAC activation are part of a single device or separable pathways. Here we characterise a novel yeast mutant, mps1-3, defective in chromosome biorientation and SAC activation. Through an unbiased screen for suppressors, we found that mutations lowering PP1 levels at Spc105 or forced association of Bub1 with Spc105 reinstate both chromosome biorientation and SAC signalling in mps1-3 cells. Our data strongly argue that Mps1-dependent phosphorylation of the Knl1/Spc105 kinetochore scaffold is critical for Mps1 function in both chromosome biorientation and SAC activation, thus supporting the idea that a common sensory apparatus simultaneously elicits error correction and SAC signalling.保守型Mps1激酶（Mps1 kinase）可纠正异常的动粒-微管附着，从而保障染色体双向定向。然而，该过程中其关键作用靶点仍未明确。Mps1还参与纺锤体组装检验点（spindle assembly checkpoint, SAC）——这是一种监视机制，可阻断染色体分离进程直至完成染色体双向定向。其在SAC激活中的作用会被PP1磷酸酶（PP1 phosphatase）拮抗，且该过程依赖于对Knl1/Spc105的磷酸化：Knl1/Spc105可招募Bub1至动粒，进而促进SAC效应复合物的组装。一个核心问题在于，错误校正与SAC激活是属于同一调控系统，还是相互独立的通路。本研究对一种新型酵母突变体mps1-3进行了表征，该突变体存在染色体双向定向与SAC激活缺陷。通过无偏向性抑制子筛选实验，我们发现，降低Spc105位点PP1水平的突变，或是将Bub1与Spc105强制结合，均可恢复mps1-3细胞中的染色体双向定向与SAC信号通路活性。我们的研究数据有力表明，Mps1依赖的Knl1/Spc105动粒支架磷酸化，对于Mps1在染色体双向定向与SAC激活中的功能均至关重要，由此支持了‘一套共同的感知装置可同时触发错误校正与SAC信号通路’这一观点。