The Nozaki Lab

Kengo Nozaki, MD, Ph.D.
Assistant Professor
College of Medicine
Department of Pharmacology and Immunology

Education
2011-2015 Ph.D., Tokyo Medical and Dental University (currently, Institute of Science Tokyo, Japan)
2015-2016 Clinical Fellow (Gastroenterology), Tokyo Medical and Dental University, Japan
2016-2020 Postdoctoral Fellow, University of North Carolina at Chapel Hill, USA
2020-2024 Research Associate Senior, Duke University School of Medicine, USA

Contact Information
Email: nozakik@musc.edu
Telephone: 843-792-8895
Office: BSB 319G

Lab Webpage
https://www.nozakilab.com/

Research Interest

Innate Sensor and Cell Death

Intestinal Epithelial Cell - Immune Cell Interaction

Organoid Engineering and Disease Modeling

Host-Pathogen Interaction

Cell Death in Cancer

Research Interests

- Danger sensing, cell death, and beyond - 

The cell death/cellular bucket list pathways should be beneficial during infection by eliminating infected cells but could be mutated and become detrimental in cancer.

The Nozaki lab aims to uncover fundamental mechanisms of intestinal immunity during infection and inflammation, especially by focusing on innate sensor, cell death and its-associated pathways (cellular bucket list, see below).

Danger sensing: Intestinal epithelial cell (IEC) is the most abundant and death-susceptible cell type in the gut. IECs are lining on the inner surface of the intestine and exposed by luminal threats. IECs can collaborate with surrounding immune cells to sense intra- and extracellular dangers such as infection, inflammation, and tumorigenic signals. We are now developing novel mouse models and organoid co-culture models, and examining immune cell – IEC interactions to identify novel danger sensing mechanisms.

Cell death: Once danger is detected, that ultimately activates cell death pathways in IECs. For example, IECs express cytosolic danger sensors such as inflammasomes (including NLRC4) that activate the pore-forming protein gasdermin D, causing a lytic cell death called pyroptosis. We previously discovered a novel mechanism to regulate pyroptosis, which controls gut immunity.

 

Caspase-7 had been considered as a weak back-up of caspase-3 for the past decades. We discovered that caspase-7 uniquely facilitates pyroptosis by activating acid-sphingomyelinase (ASM)-driven membrane repair (Nozaki, Nature, 2022). This repair pathway counteracts gasdermin D pores and delays cell lysis during pyroptosis (Fig 1), which provides enough time for completing NLRC4-driven extrusion (bucket list) of IECs during Salmonella Typhimurium infection. Failure of the caspase-7/ASM membrane repair resulted in defective extrusion in IECs (Fig 2) and severe tissue damage.

 

   

Figure 1 Figure 2

 

From this discovery of the novel mechanism to manages the time of the death, we propose a new concept: cells must complete their own “bucket lists” of tasks before they die (Fig 3) (Nozaki, Trends Cell Biol, 2023).

 

Figure 3

 

We are now focusing on discovering novel cell death/extrusion mechanisms in IECs which regulate immunological consequences.

The lab also applies the concept of bucket list to tumor cells. Tumors experience abnormal cellular stress such as CTL killing, which will trigger cell death. We aim to elucidate how cell death/bucket list pathways shape the tumor evolution and its microenvironment.

And Beyond: We think that cell death is not just the end of the story, but the initiation for the new story. The lab aims to expand our scope of cell death for the next-generation research.

 

Recent Publications

1.     Nozaki K#, Miao EA#. Bucket lists must be completed during cell death. Trends Cell Biol. 2023 Mar 22:S0962-8924(23)00040-5. doi: 10.1016/j.tcb.2023.02.008.

# Corresponding authors

2.     Nozaki K*, Maltez VI*, Rayamajhi M, Tubbs AL, Mitchell JE, Lacey CA, Harvest CK, Li L, Nash WT, Larson HN, McGlaughon BD, Moorman NJ, Brown MG, Whitmire JK, Miao EA. Caspase-7 activates ASM to repair gasdermin and perforin pores. Nature. 2022 Jun;606(7916):960-967. doi: 10.1038/s41586-022-04825-8. Epub 2022 Jun 15.

* These authors contributed equally.

3.     Nozaki K, Li L, Miao EA. Innate Sensors Trigger Regulated Cell Death to Combat Intracellular Infection. Annu. Rev. Immunol. 2022. 2022 Feb 9. doi: 10.1146/annurev-immunol-101320-011235.

4.     Nozaki K, Mochizuki W, Matsumoto Y, Matsumoto T, Fukuda M, Mizutani T, Watanabe M, Nakamura T. Co-culture with Intestinal Epithelial Organoids Allows Efficient Expansion and Motility Analysis of Intraepithelial Lymphocytes. J Gastroenterol. 2016 Mar;51(3):206-13.