Kinase-gated coincidence detection controls kinesin-driven lysosome transport

Kinesin motors drive long-range intracellular transport through coordinated cargo recognition and conformational autoregulation, yet the mechanisms that selectively control cargo engagement remain unclear. Here, we identify a phosphorylation-dependent gate on kinesin-1 activity mediated by the carboxy-terminal domain (CTD) of kinesin light chain 2 (KLC2). The KLC2 CTD is constitutively phosphorylated on multiple serine residues, suppressing membrane association via its amphipathic helix. We identify the NIMA-related kinase NEK10 as a KLC2-selective regulator of kinesin-1, restraining motor activation, cargo engagement, and lysosome transport; conversely, loss of NEK10 increases membrane association and, together with low-affinity adaptor interactions, promotes lysosome motility. These findings reveal a phosphorylation-regulated protein-lipid coincidence-detection mechanism - a kinesin-kinase code - that integrates adaptor binding with membrane cues to control kinesin-1-mediated transport and provide a mechanistic basis for understanding paralogue and isoform diversity in the kinesin-1 family. ### Competing Interest Statement The authors have declared no competing interest. Biotechnology and Biological Sciences Research Council, BB/W005581/1, BB/Z517276/1 Lister Institute of Preventive Medicine, https://ror.org/03356n642

JCI Insight - KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS

Stall force measurement of the kinesin-3 motor KIF1A using a programmable DNA origami nanospring

A DNA origami nanospring introduces a force-sensing technology that enables measurement of motor protein stall forces without optical trapping, detecting force changes in kinesin KIF1A and its disease-related mutants.

Stall force measurement of the kinesin-3 motor KIF1A using a programmable DNA origami nanospring

A DNA origami nanospring introduces a force-sensing technology that enables measurement of motor protein stall forces without optical trapping, detecting force changes in kinesin KIF1A and its disease-related mutants.

The Kifc3 Motor Protein Controls Centrosomal Factor Cep192 in Ontogenic Coordination of Megakaryocyte Development

The distinct features of neonatal megakaryocytes, high proliferation and inefficient platelet production, have clinical repercussions. A diminished capacity for stress thrombopoiesis, the response to acute drops in platelet counts, contributes to the high prevalence of thrombocytopenia in premature infants and to impaired platelet recovery after umbilical cord blood stem cell transplantation. High proliferation also promotes leukemogenesis in babies with Down Syndrome (DS). The transcriptional coactivator Mkl1/MrtfA participates in programming the ontogenic shift from fetal/neonatal to adult-type megakaryopoiesis; in this activity it is opposed by the DS-associated kinase Dyrk1a. In a screen for downstream ontogenic effectors in human progenitors, we identified the kinesin Kifc3 as a factor selectively decreased in adult megakaryocytes and whose knockdown in neonatal megakaryocytes induced adult-type morphogenesis with augmented platelet release. Kifc3 acts as a minus-end directed motor for centrosomal delivery of various cargos. Centrosomal release of Cep192 has recently been found induce cellular process extensions through actin remodeling, reminiscent of megakaryocyte platelet release. In our studies, Cep192 showed striking upregulation and dispersion in adult vs neonatal megakaryocytes, and Kifc3 knockdown recapitulated this effect in neonatal megakaryocytes. A role for Cep192 in promoting megakaryocyte morphogenesis, distinct from its role in centrosome biogenesis, was demonstrated in vitro and in vivo. In silico screening for Kifc3 inhibitors identified a small molecule that affected neonatal megakaryocytes similarly to Kifc3 knockdown, indicating feasibility for therapeutic targeting of the Kifc3-Cep192 pathway in clinical conditions associated with fetal-type megakaryopoiesis. ### Competing Interest Statement The authors have declared no competing interest. NIH, R01 HL149667, R01 DK079924, R56 DK141123