Kinesin-Binding Protein Controls Microtubule Dynamics and Cargo Trafficking by Regulating Kinesin Motor Activity

Abstract

Kinesin motor proteins play a fundamental role for normal neuronal development by controlling intracellular cargo transport and microtubule (MT) cytoskeleton organization. Regulating kinesin activity is important to ensure their proper functioning, and their misregulation often leads to severe human neurological disorders. Homozygous nonsense mutations in kinesin-binding protein (KBP)/KIAA1279 cause the neurological disorder Goldberg-Shprintzen syndrome (GOSHS), which is characterized by intellectual disability, microcephaly, and axonal neuropathy. Here, we show that KBP regulates kinesin activity by interacting with the motor domains of a specific subset of kinesins to prevent their association with the MT cytoskeleton. The KBP-interacting kinesins include cargo-transporting motors such as kinesin-3/KIF1A and MT-depolymerizing motor kinesin-8/KIF18A. We found that KBP blocks KIF1A/UNC-104-mediated synaptic vesicle transport in cultured hippocampal neurons and in C. elegans PVD sensory neurons. In contrast, depletion of KBP results in the accumulation of KIF1A motors and synaptic vesicles in the axonal growth cone. We also show that KBP regulates neuronal MT dynamics by controlling KIF18A activity. Our data suggest that KBP functions as a kinesin inhibitor that modulates MT-based cargo motility and depolymerizing activity of a subset of kinesin motors. We propose that misregulation of KBP-controlled kinesin motors may represent the underlying molecular mechanism that contributes to the neuropathological defects observed in GOSHS patients.

Dual-Color Herpesvirus Capsids Discriminate Inoculum from Progeny and Reveal Axonal Transport Dynamics

“…The high anterograde velocities (v max ϭ 2.4 m/s) measured for egressing parti- cles provide biophysical support for data from previous proteomics studies (8), indicating that the fast kinesin-3 motor Kif1A (26,27) is responsible for PRV egress. Nevertheless, the velocity profile shows a plateau rather than a single peak.…”

“…This wide distribution of observed velocities suggested that particles encounter heterogeneity in microtubule motors, motor regulatory factors, or the local axonal environment during anterograde axonal transport. The higher velocities observed were clearly distinct from those expected for kinesin-1 motors but consistent with motility driven by kinesin-3 (Kif1A), either alone or in combination with other kinesin motors (26,27). The retrograde velocity distribution during egress lacked a distinct peak but could be fitted to an overall decay trend (Fig.…”

“…The second possibility involves the differential regulation of Kif1A in different areas along the axon. Recently, a Kif1A inhibitor that is able to modulate the velocity of axonal Kif1A-driven Rab3-positive vesicles was identified (26). The third possibility is that the cargo is not driven exclusively by a single fast kinesin but also has some contribution from one or more types of slower kinesins.…”

Mechanisms and functions of lysosome positioning

“…ensconsin and DCLK1), however, promote recruitment and activation of kinesins on specific populations of microtubules (Sung et al, 2008;Lipka et al, 2016). Finally, KBPs can modulate kinesin activity, as shown for the inactivation of the motor domains of the kinesin-3 KIF1A and kinesin-8 KIF18A by the protein KBP (also known as KIF1BP and KIAA1279) (Kevenaar et al, 2016). It remains to be determined how all of these factors influence the ability of different kinesins to mediate different patterns of lysosome movement.…”

Intracellular cargo transport by kinesin-3 motors

“…Interestingly, the presence of BICD2 increases the force generation and processivity of dynein/dynactin [127,128], demonstrating that these cargo adapter proteins regulate motor activity and could act as switches to control transport directionality within a complex containing two opposing motors. Other control mechanisms could come from accessory proteins such as kinesin binding protein (KBP), which has been shown to stimulate KIF1B, but inhibit KIF1A mediated bidirec tional transport [28,129]. If the activity of such regulato ry proteins were spatially controlled, this would enable directional switching of transport complexes in the pres ence of opposing motors.…”