Research
Our Research-Nuclear pore complex (NPC)
1) NPC peripheral structural dynamics
2) NPC and its related diseases
3) Virus invasion routes to NPC
What did we discover?
I set up a lab in Kanazawa University to investigate the Nuclear pore complex (NPC) in 2008.
Major Discoveries: A Story of Supply Chains and NPC Territories
Imagine the nucleus as the central government headquarters of the cell — a heavily guarded territory that controls all genomic blueprints. At the boundary, the nuclear pore complexes (NPCs) serve as customs gates and logistics hubs, embedded within the nuclear envelope. These nano-gates control the entry and exit of critical information and cargo, shaping not just transport, but also surveillance, signaling, defense, and emergency response.
Our research journey over the past two decades can be seen as a long-term mapping of how this invisible supply chain is governed — how NPCs regulate nuclear traffic, maintain order, and respond to invasion. We have investigated the structure and function of the nuclear pore complex (NPC) for over 20 years, viewing it as a “checkpoint in the molecular supply chain.” In particular, we proposed the “Spider Cobweb” model to describe the dynamic architecture of FG-nucleoporin filaments inside the NPC (ACS Nano, 2017), revealing its functional plasticity and relevance to disease.
🚨 1: Logistics and Quality Control
We began by identifying the inner logistics regulators of the cell division process. We discovered that the nuclear pore protein Rae1 links to cohesin (SMC1) and NuMA, ensuring chromosome segregation — akin to barcode scanners verifying package contents at mitotic checkpoints.
• ▶ Rae1–Cohesin (PNAS, 2008)
• ▶ Rae1–NuMA (PNAS, 2006)
• ▶ TPR and Nup88 in mitosis (JBC, 2010)
🚨 2: Border Control and Autophagy Routes
We expanded into the autophagy pathway, finding that depletion of TPR triggers emergency degradation — like a supply depot clearing expired stock. In cancer cells, we were the first to show real-time NPC movement via HS-AFM, revealing that the nuclear border becomes porous or rigid under stress, signaling transport dysfunctions.
• ▶ Nucleoporin TPR triggers autophagy (Sci Rep, 2012)
• ▶ NPC dynamics in cancer (ACS Nano, 2017)
🚨 3: Smuggling and Invasion Surveillance
Using HS-AFM, we uncovered how viruses exploit loopholes in the nuclear border. We saw SARS-CoV-2 spike and ORF6, NSP9, and Influenza HA proteins hijack NPC traffic lanes, like hackers bypassing firewalls. Meanwhile, histone dynamics and TPR–autophagy suppression in brain tumors revealed how cargo rerouting can trigger disease. In 2018, we discovered that ROCK-dependent phosphorylation of NUP62 regulates nuclear import of the transcription factor p63 in squamous cell carcinoma, showing for the first time that cancer cells can optimize NPC composition to reinforce oncogenic transport.
• ▶ SARS-CoV-2 spike, ORF6, NSP9 (BBRC 2020, Top 10% paper; 2021 )
• ▶ HA rod-to-Y transition (Nano Letters, 2020)
• ▶ Histone H2A involution (JPCL, 2021)
• ▶ Nucleoporin TPR autophagy abnormality (Autophagy, 2021a Top 10% paper, 2021b, 2016; Top 1% papers)
• ▶ KPNA4 signaling in SCC (Oncogene, 2020, Readers's choice The best of Oncogene 2019 )
• ▶ Oncogenic transport by NPC composition change (EMBO Rep, 2018; News & View, Top 10% paper )
🚨 4: Distribution Networks and EV Logistics
We turned our attention to extracellular vesicles (EVs) — the export cargo trucks of the cell. Using HS-AFM, we visualized how EV surfaces change under stress, how neutralizing antibodies dock on viral spike-decorated EVs, and how NPCs export super-enhancers by trapping them with IDRs, like unauthorized shipments flagged by customs AI.
• ▶ EV topology and profiling ( JEV, 2022–2025, all Top 10% papers )
• ▶ Spike–EV–antibody interaction (Nano Lett., 2023)
• ▶ SE trapping by NPC (Cell Chem Biol, 2024, Top 10% paper)
🚨 5: Cargo Inspection and Interception
We zoomed in on cargo–pore interactions. Our LID model showed how estrogen receptors enter and activate genes via DNA docking — a VIP cargo with special clearance protocol. We developed the CARD model, capturing protamine-DNA packing like warehouse palletization. With these tools, we also mapped how p53 tumor suppressor is inspected by NPCs — revealing a supply chain surveillance system in glioblastoma.
• ▶ LID model (ACS Nano, 2025)
• ▶ CARD model (NAR, 2025, Top 10% paper)
• ▶ p53–NPC surveillance (Cell Rep., 2023)
🧩 Conclusion: NPC as a Smart Border and Cellular Logistics Hub
What we’ve discovered is that the NPC is far more than a passive tunnel — it is a smart border control system, equipped with surveillance, flexibility, signaling, and emergency management capabilities.
• It screens hormone signals and inspects viral invaders
• It repurposes chromatin and enhancers for cellular reprogramming
• It detects cargo defects, flags oncogenic loops, and adjusts traffic flow under stress
As global interest in spatial genome architecture, LLPS, immuno-oncology, and viral latency grows, NPCs are emerging not just as gatekeepers, but as dynamic command centers of cellular logistics.
We are now interested in how different Nups proteins interact with the genome and perform important roles in regulation of gene expression; and how different types of viruses are transported into the cell and hijacking the nuclear pores.
Research interview
"Bio-AFM
Frontier Research Center”, T. Uchihashi T. Ando
R. Wong T. Fukuma
Impact pp. 23-25, 2017