IFT88 controls NuMA enrichment at k-fibers minus-ends to facilitate their re-anchoring into mitotic spindles

Abstract

To build and maintain mitotic spindle architecture, molecular motors exert spatially regulated forces on microtubules (MT) minus-ends. This spatial regulation is required to allow proper chromosomes alignment through the organization of kinetochore fibers (k-fibers). NuMA was recently shown to target dynactin to MT minus-ends and thus to spatially regulate dynein activity. However, given that k-fibers are embedded in the spindle, our understanding of the machinery involved in the targeting of proteins to their minus-ends remains limited. Intraflagellar transport (IFT) proteins were primarily studied for their ciliary roles but they also emerged as key regulators of cell division. Taking advantage of MT laser ablation, we show here that IFT88 concentrates at k-fibers minus-ends and is required for their re-anchoring into spindles by controlling NuMA accumulation. Indeed, IFT88 interacts with NuMA and is required for its enrichment at newly generated k-fibers minus-ends. Combining nocodazole washout experiments and IFT88 depletion, we further show that IFT88 is required for the reorganization of k-fibers into spindles and thus for efficient chromosomes alignment in mitosis. Overall, we propose that IFT88 could serve as a mitotic MT minus-end adaptor to concentrate NuMA at minus-ends thus facilitating k-fibers incorporation into the main spindle.

IFT proteins interact with HSET to promote supernumerary centrosome clustering in mitosis

“…This delay could result from a delay in the assembly of the mitotic spindle. Indeed, IFT88 depletion was recently shown to be necessary for the timely insertion of the newly generated k‐fiber minus ends into the mitotic spindle and for proper chromosome alignment . Therefore, because IFT52 is essential for the stability of the IFT‐B subcomplex that includes IFT88 , it is possible that its depletion also triggers delays in spindle assembly and chromosome alignment which eventually results in an increased mitotic progression duration.…”

Intraflagellar Transport Complex B Proteins Regulate the Hippo Effector Yap1 during Cardiogenesis

“…For example, ift88 mutants display a number of phenotypes reminiscent of ciliary defects such as abnormal patterning of the neural tube, defects in the Hedgehog pathway and left-right patterning (Huang and Schier, 2009). Ift88 has also been associated with planar cell polarity (Cao et al, 2010) and cell division (Delaval et al, 2011;Taulet et al, 2017Taulet et al, , 2019Vitre et al, 2020). Our observations provide evidence for a role of IFT complex B proteins in cardiogenesis.…”

“…IFT proteins also display noncanonical, cilia-independent functions (Hua and Ferland, 2018;Vertii et al, 2015). IFT88, for example, is needed for spindle orientation and organization, cleavage furrow ingression, or extra centrosome clustering in dividing cells (Delaval et al, 2011;Taulet et al, 2017Taulet et al, , 2019Vitre et al, 2020) and regulates G1-S phase transition in nonciliated cells (Robert et al, 2007). IFT20, together with IFT88 and IFT54, plays a role in the establishment of the immune synapse in T lymphocytes lacking cilia (Finetti et al, 2009;Galgano et al, 2017).…”

Non-ciliary Roles of IFT Proteins in Cell Division and Polycystic Kidney Diseases

“…This ensures efficient enrichment of astral microtubules and proper spindle orientation (Delaval et al, 2011). More recently, IFT88 was shown to control efficient mitotic spindle dynamics in prometaphase (Taulet et al, 2019). More specifically, IFT88 is required at minus end of kinetochore-bound-microtubules to recruit the microtubule binding protein NuMA (Nuclear mitotic apparatus protein) and cytoplasmic dynein 1.…”

“…IFT proteins are, for example, involved in the regulation of microtubule dynamics and/or organization in interphase cells ( Bizet et al, 2015 ; Boehlke et al, 2015 ; Dupont et al, 2019 ). They are also required for specialized cellular functions such as the formation of the immune synapse in T cells ( Finetti et al, 2009 , 2014 ), the inflammatory response ( McFie et al, 2020 ), the regulation of cell cycle progression ( Robert et al, 2007 ) or cell division ( Jonassen et al, 2008 ; Delaval et al, 2011 ; Borovina and Ciruna, 2013 ; Taulet et al, 2017 , 2019 ; Vitre et al, 2020 ). We will summarize here our current knowledge on how IFT proteins interact and regulate microtubules and motors.…”