权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Characterizing the Mechanism of DPP8/9 Inhibitor-Induced Pyroptosis

DPP8/9 抑制剂诱导细胞焦亡机制的表征

基本信息

批准号：
10733874
负责人：
Daniel Bachovchin
金额：
$ 52.38万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-23 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733874
关键词：
Acceleration Affect Amino Acid Sequence Amino Acids Area Autoimmune Diseases Biology C-terminal Cancer Etiology Cell Death Cells Cellular Metabolic Process Cellular Structures Communicable Diseases Complex Cysteine Data Dipeptides Dipeptidyl Peptidases Disease Foundations Future Health Homeostasis Human Immune response Immunity Inflammasome Inflammatory Innate Immune System Knowledge Laboratories Length Ligand Binding Link Lytic Malignant Neoplasms Mass Spectrum Analysis Mediating Metabolic Metabolic Diseases Metabolic dysfunction Mitochondria Molecular Monitor Multiprotein Complexes N-terminal Natural Immunity Neurodegenerative Disorders Oxidation-Reduction Paper Pattern recognition receptor Peptides Play Printing Process Proline Protein Region Proteins Proteomics Public Health Reactive Oxygen Species Reporting Repression Research Research Project Grants Serine Signal Transduction Stress T-Lymphocyte Therapeutic Work disulfide bond human disease inhibitor multicatalytic endopeptidase complex pathogen peptidomimetics protein degradation receptor binding small molecule

项目摘要

PROJECT SUMMARY Several human pattern-recognition receptors detect intracellular danger-associated signals, oligomerize into multiprotein complexes called inflammasomes, and trigger a lytic form of cell death called pyroptosis. Inflammasomes are involved in mounting immune responses to pathogens and in maintaining organismal homeostasis, but their hyperactivation can cause cancer, autoimmune disorders, and metabolic dysfunction. As such, it is critically important to characterize the molecular mechanisms that regulate inflammasome activation. NLRP1 and CARD8 are related pattern-recognition receptors that form inflammasomes, but the danger signals that they sense have not been fully established. Notably, ligands that bind to the serine dipeptidyl peptidases 8 and 9 (DPP8/9), including endogenous peptides with Xaa-Pro (where Xaa is any amino acid) N-termini, have been reported to activate these inflammasomes. However, why the innate immune system monitors Xaa-Pro peptide levels is unknown and constitutes a major knowledge gap. Recently, reductive stress, or a profound lack of reactive oxygen species (ROS), was also reported to activate the NLPR1 and CARD8 inflammasomes. The central hypothesis of this application is that reductive stress and Xaa-Pro peptide accumulation are intimately related danger signals that together comprise an overall “danger state” that causes rapid and full NLRP1 and CARD8 inflammasome activation. Specifically, it is proposed that the disordered regions of many cytosolic proteins, including the autoinhibitory N-terminal region of CARD8, are stabilized by intramolecular disulfide bonds; reductive stress abolishes these bonds, destabilizing these sequences and triggering their degradation into peptides by the proteasome. Proline is the most abundant amino acid in disordered protein regions, and therefore reductive stress likely generates many Xaa-Pro peptides. In this way, Xaa-Pro peptide accumulation can serve to confirm that reductive stress is occurring. This central hypothesis has been formulated based on preliminary data produced in the applicant’s laboratory and described in this application. The objective of this project is to determine the relationship between reductive stress, disordered protein degradation, and Xaa-Pro peptide accumulation. This project consists of three Specific Aims: 1) to determine how reductive stress induces the proteasome-mediated degradation of CARD8, 2) to characterize the relationship between reductive stress and Xaa-Pro peptide accumulation, and 3) to determine the relationship between cell metabolism and inflammasome activation. The successful completion of this work will not only clarify the primordial function of these enigmatic inflammasomes, but will also reveal a previously unknown a connection between intracellular redox state and protein stability. Moreover, this work will provide the foundation for future efforts to therapeutically control these inflammasomes for the treatment of human disease.

项目总结

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protein folding stress potentiates NLRP1 and CARD8 inflammasome activation.

DOI：
10.1016/j.celrep.2022.111965
发表时间：
2023-01
期刊：
Cell reports
影响因子：
8.8
作者：
Elizabeth L. Orth-He;Hsin-Che Huang;Sahana D. Rao;Qinghui Wang;Qifeng Chen;Claire M. O’Mara;Ashley J. Chui;Michelle Saoi;A. R. Griswold;A. Bhattacharjee;D. Ball;J. Cross;D. Bachovchin
通讯作者：
Elizabeth L. Orth-He;Hsin-Che Huang;Sahana D. Rao;Qinghui Wang;Qifeng Chen;Claire M. O’Mara;Ashley J. Chui;Michelle Saoi;A. R. Griswold;A. Bhattacharjee;D. Ball;J. Cross;D. Bachovchin

DPP8/9 are not Required to Cleave Most Proline-Containing Peptides.

切割大多数含脯氨酸的肽不需要 DPP8/9。

DOI：
10.1002/ijch.202200117
发表时间：
2023
期刊：
Israel journal of chemistry
影响因子：
3.2
作者：
Bhattacharjee,Abir;Bachovchin,DanielA
通讯作者：
Bachovchin,DanielA

Activation of the CARD8 Inflammasome Requires a Disordered Region.

DOI：
10.1016/j.celrep.2020.108264
发表时间：
2020-10-13
期刊：
Cell reports
影响因子：
8.8
作者：
Chui AJ;Griswold AR;Taabazuing CY;Orth EL;Gai K;Rao SD;Ball DP;Hsiao JC;Bachovchin DA
通讯作者：
Bachovchin DA

The NLRP1 and CARD8 inflammasomes detect reductive stress.

NLRP1和CARD8炎症体检测还原应力。