The CUL3-KLHL18 ligase regulates mitotic entry and ubiquitylates Aurora-A
Saili Moghe,
Fei Jiang,
Yoshie Miura,
Ronald L. Cerny,
Ming-Ying Tsai,
Manabu Furukawa
Affiliations
Saili Moghe
Eppley Institute for Research in Cancer and Allied Diseases, 987696 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
Fei Jiang
Eppley Institute for Research in Cancer and Allied Diseases, 987696 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
Yoshie Miura
Eppley Institute for Research in Cancer and Allied Diseases, 987696 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
Ronald L. Cerny
University of Nebraska, Lincoln, Nebraska 68588, USA
Ming-Ying Tsai
Eppley Institute for Research in Cancer and Allied Diseases, 987696 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
Manabu Furukawa
Eppley Institute for Research in Cancer and Allied Diseases, 987696 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
Summary The cullin-RING family of ubiquitin ligases regulates diverse cellular functions, such as cell cycle control, via ubiquitylation of specific substrates. CUL3 targets its substrates through BTB proteins. Here we show that depletion of CUL3 and the BTB protein KLHL18 causes a delay in mitotic entry. Centrosomal activation of Aurora-A, a kinase whose activity is required for entry into mitosis, is also delayed in depleted cells. Moreover, we identify Aurora-A as a KLHL18-interacting partner. Overexpression of KLHL18 and CUL3 promotes Aurora-A ubiquitylation in vivo, and the CUL3-KLHL18-ROC1 ligase ubiquitylates Aurora-A in vitro. Our study reveals that the CUL3-KLHL18 ligase is required for timely entry into mitosis, as well as for the activation of Aurora-A at centrosomes. We propose that the CUL3-KLHL18 ligase regulates mitotic entry through an Aurora-A-dependent pathway.
