Research Laboratories
CELL BIOLOGY and BIOCHEMISTRY (Hiroyuki Kawahara, Tetsuhisa Otani, Naoto Yokota)
Research Overview
Our laboratory specializes in integrating biochemical and genetic experimental approaches to understand the processes within living systems. We identify and analyze novel gene products involved in cell proliferation, differentiation, tumorigenesis, and cell death, with the ultimate goal of understanding these processes and their roles in the overall regulation of cellular function. We want to open up new fields, from basic biology at the cellular level, where many aspects remain unexplored, to various applied research including work in the clinical setting.
Specifically, we are currently focused on the following themes:
- Selective degradation mechanism of membrane proteins via preemptive quality control
- Novel functional regulation of small GTPases through ubiquitination
- Mechanisms of cell cycle regulation mediated by RNA-binding proteins
- Making, maintaining, manipulating cell junctions
If you are interested in joining the graduate program and doing research with us, please contact us through email.
Current Projects
(1) Selective degradation mechanism of membrane proteins via preemptive quality control
Preemptive quality control system is a crucial cellular mechanism that prevents the accumulation of defective membrane and secretory proteins in the cytoplasm. During protein biosynthesis, occasional errors such as defective mRNA splicing or abnormal protein targeting can result in misfolded polypeptides prone to aggregations. Without an effective clearing system, the aggregations can become pathological and lead to many diseases such as neurodegeneration, immune disorders, and other pathologies. The recognition and degradation of these aberrant proteins is thus extremely important for maintaining homeostasis in the body, but most of the molecular mechanisms regulating this system remain largely unknown.
When membrane or secretory proteins are newly synthesized, they have to travel from the rough endoplasmic reticulum towards the membrane in a complex process otherwise known as protein trafficking. In some cases (e.g. high stress conditions), the proteins are not properly recognized and transported, leading to them becoming stuck in the cytoplasm where they can form pathological aggregations. To combat this aggregation, it has been suspected that a cytoplasmic degradation pathway, which was called "pre-emptive protein quality control", is at play. Through our work, we have been able to identify BAG6 (a ubiquitin-like protein) as a critical player in this process, being able to demonstrate that it specifically recognizes structurally-defective newly synthesized polypeptides and helps recruit them to the proteasome system. At present, we continue to further understand the molecular mechanisms and biological significance of the preemptive quality control system centered on BAG6.
(2) Novel functional regulation of small GTPases through ubiquitination
The pre-emptive quality control system plays a key role in maintaining cellular homeostasis by preventing the accumulation of defective proteins. While small GTPases like Rab proteins are known for their role in membrane trafficking, little was understood about how their inactive, GDP-bound forms are regulated. Through our work, we identified BAG6 as a central factor in selectively degrading GDP-bound Rab8a via the proteasome, preventing its accumulation in the cytoplasm. This discovery reveals a previously unknown regulatory aspect of small GTPases and suggests that BAG6 dysfunction may contribute to organelle trafficking defects and disease pathology. Given that many small GTPases share high sequence similarity and are implicated in various diseases, we are further investigating the role of BAG6 in maintaining organelle homeostasis and its broader impact on cellular function.
(3) Mechanisms of cell cycle regulation mediated by RNA-binding protein
mRNA quality control is essential for regulating gene expression. We identified have been able to identify the ZFP36 protein family, which are CCCH-type zinc-finger proteins, as a key players in meiotic progression and later on found its role in controlling the G1/S transition in human cells. ZFP36 levels peak at G1/S and increase further under DNA damage, suppressing G1 cyclin mRNAs to induce cell cycle arrest. While previously thought to function only in the cytoplasm, ZFP36 have been found to also accumulate in the nucleus at G1/S, suggesting undiscovered nuclear functions which we are keen to explore further.
(4) Making, maintaining, manipulating cell junctions
The Otani group is interested in understanding cell-cell junctions, which are essential for maintaining the integrity and homeostasis of epithelial tissue. We investigate how tight junctions (TJs), adherens junctions (AJs) and desmosomes form, how they contribute to the function, physiology, and molecular organization of the epithelial barrier. In particular, we are interested in the following:
- determine how tight junctions regulate mechanical resistance with focus on the mechanosensor molecule ZO-1
- understand how cell competition, a phenomenon where minute mutant cells are eliminated by neighboring normal cells, is regulated by cell-cell junctions and contribute to epithelial tissue homeostasis
- deduce the molecular organization of intercellular adhesion by developing techniques to artificially create cell-cell adhesion
Staff Highlight
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Dr. Hiroyuki Kawahara (川原 裕之) Professor | Dr. Tetsuhisa Otani (大谷 哲久) Associate Professor | Dr. Naoto Yokota (横田 直人) Assistant Professor |
Email: | ||
hkawa[at]tmu.ac.jp | otani[at]tmu.ac.jp | nyokota[at]tmu.ac.jp |
| Read more: | ||
Lab Information: | ||
Recent Publications
1. TanGIBLE: A selective probe for evaluating hydrophobicity-exposed defective proteins in live cells
Yasuyuki Iwasa, Sohtaroh Miyata, Takuya Tomita, Naoto Yokota, Maho Miyauchi, Ruka Mori, Shin Matsushita, Rigel Suzuki,
Yasushi Saeki, Hiroyuki Kawahara. Journal of Cell Biology, 224(3) e202109010, Jan 2025
2. Vertex remodeling during epithelial morphogenesis
Kaoru Sugimura, Tetsuhisa Otani. Current Opinion in Cell Biology, 91 102427-102427, Dec 2024
3. Tight junction membrane proteins regulate the mechanical resistance of the apical junctional complex
Thanh Phuong Nguyen, Tetsuhisa Otani, Motosuke Tsutsumi, Noriyuki Kinoshita, Sachiko Fujiwara, Tomomi Nemoto,
Toshihiko Fujimori, Mikio Furuse. Journal of Cell Biology, 223(5) e202307104, May 2024
4. Mechanism of interdigitation formation at apical boundary of MDCK cell
Shintaro Miyazaki, Tetsuhisa Otani, Kei Sugihara, Toshihiko Fujimori, Mikio Furuse, Takashi Miura,
iScience, 26(5) 106594, Apr 2023
5. BAG6 supports stress fiber formation by preventing the ubiquitin-mediated degradation of RhoA
Maho Miyauchi, Reina Matsumura, Hiroyuki Kawahara, Molecular Biology of the Cell, 34(4), Mar 2023
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