Research
(Figure 2)
(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 causing cell death such as CTL killing. We aim to elucidate how cell death/bucket list pathways shape the tumor evolution and its microenvironment by using unique in vitro and in vivo colon tumor models, and how those mechanisms can be applied to therapeutics.
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. We are now investigating novel mechanisms after cell death in various settings.
We will keep moving forward and never stop challenging!
-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.
Danger sensing
(Figure 1)
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. By communicating with surrounding immune cells, IECs can sense intra- and extracellular dangers such as infection, inflammation, and tumorigenic signals. However, how IECs interact with other immune cells to amplify their danger detection remains elusive. We are now developing novel mouse models and organoid 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.
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).