Mitotic catastrophe (MC) is an important oncosuppressive mechanism that serves to eliminate cells that become polyploid or aneuploid due to aberrant mitosis. Previous studies have demonstrated that the activation and catalytic function of caspase-2 are key steps in MC to trigger apoptosis and/or cell cycle arrest of mitotically defective cells. However, the molecular mechanisms that regulate caspase-2 activation and its function are unclear. Here, we identify six new phosphorylation sites in caspase-2 and show that a key mitotic kinase, Aurora B kinase (AURKB), phosphorylates caspase-2 at the highly conserved residue S384. We demonstrate that phosphorylation at S384 blocks caspase-2 catalytic activity and apoptosis function in response to mitotic insults, without affecting caspase-2 dimerisation. Moreover, molecular modelling suggests that phosphorylation at S384 may affect substrate binding by caspase-2. We propose that caspase-2 S384 phosphorylation by AURKB is a key mechanism that controls caspase-2 activation during mitosis.

有丝分裂灾难 (MC) 是一种重要的肿瘤抑制机制，用于消除由于异常有丝分裂而变成多倍体或非整倍体的细胞。先前的研究表明，caspase-2 的激活和催化功能是 MC 中触发有丝分裂缺陷细胞凋亡和/或细胞周期停滞的关键步骤。然而，调节 caspase-2 激活及其功能的分子机制尚不清楚。在这里，我们确定了 caspase-2 中的六个新磷酸化位点，并表明关键的有丝分裂激酶 Aurora B 激酶 (AURKB) 在高度保守的残基 S384 处磷酸化 caspase-2。我们证明 S384 处的磷酸化会阻止 caspase-2 催化活性和细胞凋亡功能以响应有丝分裂损伤，而不影响 caspase-2 二聚化。而且，分子模型表明 S384 处的磷酸化可能会影响 caspase-2 的底物结合。我们认为 AURKB 对 caspase-2 S384 的磷酸化是控制有丝分裂过程中 caspase-2 激活的关键机制。