The long-term objective of this application is to understand the roles and mechanisms of caspase-11 in regulating patho-physiological processes. Caspase-11, originally named ICH-3, is a member of the caspase-1 subfamily of cysteine proteases. Caspase-11 has been shown to play critical roles in innate immune responses by regulating cytokine maturation and in apoptosis. Recently it was found that caspase-11 also plays an important role in regulating cell migration during acquired immune responses. Thus, caspase-11 may serve as a novel link between innate and acquired immune responses. This proposal is to explore the mechanism by which caspase-11 regulates cell migration and the mechanism that specifies the activation of different downstream pathways of caspase-11 in patho-physiological responses.
Specific Aim I is to elucidate the molecular mechanism by which caspase-11 regulates activated lymphocyte and macrophage migration in immune responses. This is to determine if caspase-11 regulates cell migration through a cell autonomous mechanism by regulating levels of key signal transduction molecules or cell non-autonomous mechanism by regulating key cytokine secretion.
Specific Aim II is to determine the molecular mechanism of caspase-11 activation and specification in regulating cytokine release, activated immune cell migration and apoptosis. The hypothesis is that caspase-11 exists in different protein complexes in a concentration, time or cell type-dependent manner during immune and inflammatory responses depending on the levels of caspase-11 and the interacting proteins that dictate whether to activate apoptosis, cytokine release or limit lymphocyte migration.
Specific Aim I ll is to determine the molecular mechanism of caspase-11 induction. The expression of caspase-1 I may be regulated by NF-kB and STAT1 pathways.
This Specific Aim will test the hypothesis that STATI regulates the basal expression of caspase-11, which is required for the induction of caspase-11, while the latter is regulated mainly through the NF-kB pathway. These studies will provide new molecular insights into the mechanism by which innate immune response participates in acquired immune responses and create new therapeutic options for infectious and autoimmune diseases. This work will also provide novel insights into the non-apoptotic function of caspases, which are directly relevant for development of caspase inhibitors as drugs for treatment of human diseases.
| Vakifahmetoglu-Norberg, Helin; Xia, Hong-guang; Yuan, Junying (2015) Pharmacologic agents targeting autophagy. J Clin Invest 125:5-13 |
| Mou, Jianfeng; Park, Ann; Cai, Yu et al. (2015) Structure-activity relationship study of E6 as a novel necroptosis inducer. Bioorg Med Chem Lett 25:3057-61 |
| Xiao, Juan; Zhang, Tao; Xu, Daichao et al. (2015) FBXL20-mediated Vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation. Genes Dev 29:184-96 |
| Zhang, Tao; Dong, Kangyun; Liang, Wei et al. (2015) G-protein-coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L. Elife 4:e06734 |
| Xu, Daichao; Zhang, Tao; Xiao, Juan et al. (2015) Modification of BECN1 by ISG15 plays a crucial role in autophagy regulation by type I IFN/interferon. Autophagy 11:617-28 |
| Zhou, Wen; Yuan, Junying (2014) Necroptosis in health and diseases. Semin Cell Dev Biol 35:14-23 |
| Py, Bénédicte F; Jin, Mingzhi; Desai, Bimal N et al. (2014) Caspase-11 controls interleukin-1? release through degradation of TRPC1. Cell Rep 6:1122-1128 |
| Degterev, Alexei; Zhou, Wen; Maki, Jenny L et al. (2014) Assays for necroptosis and activity of RIP kinases. Methods Enzymol 545:1-33 |
| Py, Bénédicte F; Kim, Mi-Sung; Vakifahmetoglu-Norberg, Helin et al. (2013) Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell 49:331-8 |
| Wu, Zhijie; Li, Ying; Cai, Yu et al. (2013) A novel necroptosis inhibitor-necrostatin-21 and its SAR study. Bioorg Med Chem Lett 23:4903-6 |
Showing the most recent 10 out of 47 publications
