Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells

Abstract

When a T cell and an antigen-presenting cell form an immunological synapse, rapid dynein-driven translocation of the centrosome toward the contact site leads to reorganization of microtubules and associated organelles. Currently, little is known about how the regulation of microtubule dynamics contributes to this process. Here, we show that the knockout of KIF21B, a kinesin-4 linked to autoimmune disorders, causes microtubule overgrowth and perturbs centrosome translocation. KIF21B restricts microtubule length by inducing microtubule pausing typically followed by catastrophe. Catastrophe induction with vinblastine prevented microtubule overgrowth and was sufficient to rescue centrosome polarization in KIF21B-knockout cells. Biophysical simulations showed that a relatively small number of KIF21B molecules can restrict mirotubule length and promote an imbalance of dynein-mediated pulling forces that allows the centrosome to translocate past the nucleus. We conclude that proper control of microtubule length is important for allowing rapid remodeling of the cytoskeleton and efficient T cell polarization.

Kinesin-4 Motor Teams Effectively Navigate Dendritic Microtubule Arrays Through Track Switching and Regulation of Microtubule Dynamics

“…As the native MT code and cytoskeletal organization of extracted dendrites was insufficient to establish a retrograde bias for KIF21B motors that paralleled that observed in live cell assays (Ghiretti et al, 2016), we wondered whether the key factor missing from our assay might be MT dynamics. Previous work (Ghiretti et al, 2016;Hooikaas et al, 2020;van Riel et al, 2017) and our current studies indicate that KIF21B has the ability to modulate MT dynamics both in vitro and in vivo. This modulation may contribute to the establishment of a net retrograde bias for KIF21B-driven cargos moving along mammalian dendrites as KIF21B could influence the dynamics of specific populations of MTs oriented plus-end in over those oriented plus-end out based on differences in stability.…”

“…and T-cells indicate that KIF21B is involved in stabilizing MTs (Ghiretti et al, 2016;Hooikaas et al, 2020). However, in vitro experiments testing the effect of KIF21B on MT dynamics have produced different results depending on assay conditions (Ghiretti et al, 2016;van Riel et al, 2017).…”

“…Dimeric motor domain constructs lacking the C-terminal MTRs move processively toward the MT plus-end while the MTRs bind to MTs independently of the motor domain (Ghiretti et al, 2016;van Riel et al, 2017). The MTRs have been shown to dampen or pause MT dynamics (Ghiretti et al, 2016;Hooikaas et al, 2020;van Riel et al, 2017), but the magnitude of these effects differs depending on experimental conditions. A possible role for the MTRs in controlling directionality and processivity of cargo trafficking has not been explored.In this study, we investigated how KIF21B motors establish long-range transport on mixed polarity MT networks.…”

Dynein self-organizes while translocating the centrosome in T-cells

“…Although it is known that centrosome translocation is mediated by dynein motors, it is still elusive how this organization is precisely orchestrated and what role the MT network and associated proteins play ( Kuhn and Poenie, 2002 ; Combs et al. , 2006 ; Hooikaas et al. , 2020 ).…”

Immune Cell Degranulation in Fungal Host Defence

“…Specifically, terminal transport of lytic granules to the tumor IS is mediated by the kinesin-1/Slp3/Rab27a complex where kinesin-1 is essential for the final terminal movement of granules toward the IS [ 42 ]. Kinesin-4 was found to be important in regulating microtubule growth to allow for rapid remodeling and polarization of the microtubules when CD8+ T cells are in contact with antigen presenting cells [ 96 ]. However, the role of kinesin-4 is unclear in CD8+ T cell cytotoxic mechanisms.…”