Intracellular transport is a vital process that allows cells to move proteins and other molecules to specific locations. This process is especially important in neurons, which have highly polarized structures with long extensions such as axons and dendrites. For neurons to function properly, proteins must be transported accurately to specific regions, such as the axon initial segment (AIS), a specialized site for initiating electrical signals. Despite its importance, how motor proteins selectively recognize and transport specific cargo molecules has remained an open question in cell biology.
Kinesin superfamily proteins (KIFs) are microtubule-dependent molecular motors that drive intracellular transport by carrying diverse cargo, including organelles and signaling molecules, along cellular tracks. Among these, the kinesin-2 family typically consists of KIF3A, KIF3B, and kinesin-associated protein 3 (KAP3). However, it remains unclear whether variations in their assembly influence cargo selectivity.
In a recent study, a team of researchers led by Professor Nobutaka Hirokawa from the Graduate School of Medicine, Juntendo University, Japan, along with Dr. Xuguang Jiang, a JSPS Postdoctoral Fellow, Dr. Sotaro Ichinose from Gunma University, Japan, and Dr. Tadayuki Ogawa from Dokkyo Medical University, Japan, discovered a previously unrecognized mechanism that regulates cargo-specific transport in neurons. The study was published online on March 30, 2026, and is scheduled to be published in Volume 225, Issue 5 of the Journal of Cell Biology on May 04, 2026.
Explaining the motivation behind the study, Prof. Hirokawa says, “While many studies have revealed how kinesin motor proteins move along microtubules, a key unanswered question has been how they recognize and selectively transport specific cargo molecules.” He adds, “Neurons provide a particularly compelling system to study this because they require extremely precise intracellular transport to maintain their highly polarized structure.”
In this vein, the research team employed a combination of neuronal cell biology, biochemical reconstitution, and structural analyses. Using cultured neurons and mouse brain samples, they examined the composition and distribution of kinesin-2 motor complexes. They also used gene knockdown and knockout approaches to evaluate the role of specific motor components in transporting TRIM46, a protein that accumulates at the AIS and is essential for establishing neuronal polarity.
Their findings revealed that kinesin-2 is not a single, uniform motor complex. Instead, it forms multiple molecular subtypes with distinct compositions and functions. In addition to the canonical KIF3A/B/KAP3 complex, the researchers identified a KIF3B/B/KAP3 complex that preferentially associates with TRIM46 and facilitates its transport to the AIS. Importantly, when KIF3B was depleted, TRIM46 failed to accumulate properly at the AIS, even though its overall levels within the cell remained unchanged. This indicated that the defect arises from impaired transport rather than reduced protein production. Further structural analyses suggested that differences in the tail domains of these motor complexes may determine their cargo-binding specificity.
Beyond advancing fundamental understanding, the study also has important implications for human health. Defects in intracellular transport are associated with a wide range of neurological and neurodevelopmental disorders. Proper delivery of proteins, such as TRIM46, is essential for maintaining neuronal polarity, synaptic function, and neural circuit formation.
Emphasizing the broader impact, Prof. Hirokawa says, “By identifying how kinesin-2 motors selectively transport proteins to specific neuronal regions, our study provides important insights into the molecular mechanisms that organize neuronal architecture.” He adds, “In the long term, understanding how motor proteins recognize and deliver specific cargo could help guide the development of therapeutic strategies targeting transport defects.”
In addition to its relevance in neuroscience, this work contributes to a broader understanding of intracellular transport systems. The discovery that motor protein composition can regulate cargo specificity introduces a new conceptual framework for studying how cells organize their internal logistics. These insights may also inspire future applications in biotechnology and nanotechnology, where engineered systems mimic biological transport processes.
Overall, this study demonstrates that diversity in motor protein assemblies plays a crucial role in achieving precise intracellular transport. By uncovering how neurons regulate cargo delivery with such specificity, these findings provide fresh insights into neuronal development and disease.
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Reference
Authors: Xuguang Jiang 1 , Sotaro Ichinose 2 , Tadayuki Ogawa 3 , Kento Yonezawa 4,5 , Nobutaka Shimizu 4,6 , and Nobutaka Hirokawa 1,7
DOI: 10.1083/jcb.202503138
Affiliations: 1 Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
2 Department of Anatomy, Graduate School of Medicine, Gunma University, Gunma, Japan
3 Laboratory for Molecular Pathobiology, Research Center for Advanced Medical Science, Dokkyo Medical University, Tochigi, Japan
4 Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Ibaraki, Japan
5 Center for Digital Green-innovation, Nara Institute of Science and Technology, Nara, Japan
6 Life Science Research Infrastructure Group, Advanced Photon Technology Division, RIKEN SPring-8 Center, Hyogo, Japan
7 Graduate School of Medicine, Juntendo University, Tokyo, Japan
About Professor Nobutaka Hirokawa from the Graduate School of Medicine, Juntendo University, Japan
Professor Nobutaka Hirokawa is a prominent molecular cell biologist and neuroscientist at the Graduate School of Medicine, Juntendo University, Japan. He obtained his MD (1971) and PhD (1978) from the University of Tokyo Medical School and has over 40 years of research experience. Dr. Hirokawa has authored 444 publications. His research focuses on intracellular transport, kinesin motor proteins, and neuronal development. He is best known for discovering the kinesin superfamily and elucidating its roles in neuronal function, brain wiring, and disease. He has received numerous honors, including the Japan Academy Prize and Japan’s Order of Culture.
History of Juntendo University
Juntendo was originally founded in 1838 as a Dutch School of Medicine at a time when Western medical education was not yet embedded as a normal part of Japanese society. With the creation of Juntendo, the founders hoped to create a place where people could come together with the shared goal of helping society through the powers of medical education and practices. Their aspirations led to the establishment of Juntendo Hospital, the first private hospital in Japan. Through the years the institution's experience and perspective as an institution of higher education and a place of clinical practice has enabled Juntendo University to play an integral role in the shaping of Japanese medical education and practices. Along the way the focus of the institution has also expanded, now consisting of nine undergraduate programs and six graduate programs, the university specializes in the fields of health science, health and sports science, nursing health care and sciences, and international liberal arts, as well as medicine. Today, Juntendo University continues to pursue innovative approaches to international level education and research with the goal of applying the results to society.
Mission Statement
The mission of Juntendo University is to strive for advances in society through education, research, and healthcare, guided by the motto “Jin – I exist as you exist” and the principle of “Fudan Zenshin - Continuously Moving Forward”. The spirit of “Jin”, which is the ideal of all those who gather at Juntendo University, entails being kind and considerate of others. The principle of “Fudan Zenshin” conveys the belief of the founders that education and research activities will only flourish in an environment of free competition. Our academic environment enables us to educate outstanding students to become healthcare professionals patients can believe in, scientists capable of innovative discoveries and inventions, and global citizens ready to serve society.
Journal of Cell Biology
Experimental study
Cells
The KIF3B/B/KAP3 tail domain specifically facilitates TRIM46 transport to the axon initial segment
4-May-2026
The authors declare that no competing interests exist.