Abstract
Centrosome amplification is a hallmark of cancer, and centrosome clustering is essential for cancer cell survival. The mitotic kinesin HSET is an essential contributor to this process. Recent studies have highlighted novel functions for intraflagellar transport (IFT) proteins in regulating motors and mitotic processes. Here, using siRNA knock‐down of various IFT proteins or AID‐inducible degradation of endogenous IFT88 in combination with small‐molecule inhibition of HSET, we show that IFT proteins together with HSET are required for efficient centrosome clustering. We identify a direct interaction between the kinesin HSET and IFT proteins, and we define how IFT proteins contribute to clustering dynamics during mitosis using high‐resolution live imaging of centrosomes. Finally, we demonstrate the requirement of IFT88 for efficient centrosome clustering in a variety of cancer cell lines naturally harboring supernumerary centrosomes and its importance for cancer cell proliferation. Overall, our data unravel a novel role for the IFT machinery in centrosome clustering during mitosis in cells harboring supernumerary centrosomes.
Highlights
The centrosome is a dynamic organelle that has essential functions in both cycling and non-cycling cells
Taking advantage of high-resolution imaging of centrosome dynamics, we show that IFT52 knock-down decreases centrosome clustering dynamics, both in late G2 and in mitosis, to the same extent as HSET small-molecule inhibition
IFT88 and IFT52 are required for centrosome clustering
Summary
The centrosome is a dynamic organelle that has essential functions in both cycling and non-cycling cells. Multiple studies have highlighted the importance of the mitotic checkpoint and the actin/ microtubule networks, together with their associated proteins and motors, for efficient centrosome clustering [9,13,17,18] Among those microtubule-associated motors, the minus-end-directed kinesin HSET/KIFC1 is of particular interest, since it is essential for supernumerary centrosome clustering but not for the division of cells with two centrosomes [9,13,19,20,21]. IFT88 in complex with cytoplasmic dynein 1 contributes to the relocalization of peripheral microtubule clusters toward the spindle poles to ensure the proper formation of astral microtubule arrays and correct spindle orientation [33] Similarities between this latter mechanism and the process of centrosome clustering, per se, led us to hypothesize that IFT proteins could contribute to centrosome clustering in cells harboring supernumerary centrosomes. Our data unravel a novel role for the IFT machinery in centrosome clustering during mitosis in cells harboring supernumerary centrosomes
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