Regulated proteolysis by the ubiquitin-proteasome system (ubiquitin system) plays essential roles in a multitude of biological processes and has major ramifications for human health and disease, including illnesses that range from cancer and neurodegeneration to cardiovascular syndromes and defects of immunity. Our studies of the ubiquitin-proteasome system and ubiquitin-dependent N-degron pathways (previously called ?N-end rule pathways?) over more than three decades were made possible, to a large extent, by the present grant (GM031530), currently in its 37th year of support. N-degron pathways recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, polyubiquitylate these proteins and thereby cause their degradation by the proteasome or autophagy. Recognition components of N-degron pathways, called N-recognins, are E3 ubiquitin ligases that can target N-degrons. One eukaryotic N-degron pathway, called the Arg/N-degron pathway, targets specific unacetylated Nt-residues of protein substrates. This pathway, discovered by our laboratory in 1986, continues to be a fount of biological insights. The Ac/N-degron pathway, discovered by our laboratory in 2010, recognizes proteins that bear N-terminally acetylated residues. The other two proteolytic systems, the Pro/N-degron pathway and the fMet/N-degron pathway, are mediated, respectively, by the E3s GID and Psh1, and recognize, respectively, the Nt-proline (Pro) and the Nt-formyl-Met (fMet) residues of protein substrates. This resubmitted GM031530 renewal application stems from our unpublished studies over the last ~2 years, contains results obtained the last ~10 months as well, and focuses on the mammalian Arg/N-degron pathway, including the recently discovered ability of its E3s Ubr1/Ubr2 to bind to transcriptional factors (TFs) Atf3, Fosl1, c-Fos, Fosl1, Prep1, and Prep2. Beginning with Atf3, we recently showed that, in vivo, the binding of Atf3 to Ubr1/Ubr2 results in the degradation of Atf3 by the Arg/N-degron pathway. These and other (related) studies, described in Specific Aims of the resubmitted GM031530 renewal application, will advance the understanding of protein degradation and the universally present (as well as medically significant) Arg/N-degron pathway.

Public Health Relevance

Studies proposed in this renewal application for the GM031530-37 grant will address regulated protein degradation by the mammalian Arg/N-degron pathway, a proteolytic system universal among fungi, protists, animals and plants. Inborn or acquired defects in proteolytic systems are a major cause of many human diseases, including cancer, infections, cardiovascular illnesses and neurodegenerative syndromes. Our studies of the Arg/N-degron pathway, a specific ubiquitin-dependent proteolytic system, will contribute to advances in fundamental biology, and may lead to better therapies for specific medical problems.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM031530-38A1
Application #
9879276
Study Section
Membrane Biology and Protein Processing Study Section (MBPP)
Program Officer
Barski, Oleg
Project Start
1992-07-01
Project End
2023-11-30
Budget Start
2019-12-10
Budget End
2020-11-30
Support Year
38
Fiscal Year
2020
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Kim, Jeong-Mok; Seok, Ok-Hee; Ju, Shinyeong et al. (2018) Formyl-methionine as an N-degron of a eukaryotic N-end rule pathway. Science 362:
Oh, Jang-Hyun; Chen, Shun-Jia; Varshavsky, Alexander (2017) A reference-based protein degradation assay without global translation inhibitors. J Biol Chem 292:21457-21465
Oh, Jang-Hyun; Hyun, Ju-Yeon; Varshavsky, Alexander (2017) Control of Hsp90 chaperone and its clients by N-terminal acetylation and the N-end rule pathway. Proc Natl Acad Sci U S A 114:E4370-E4379
Chen, Shun-Jia; Wu, Xia; Wadas, Brandon et al. (2017) An N-end rule pathway that recognizes proline and destroys gluconeogenic enzymes. Science 355:
Wadas, Brandon; Piatkov, Konstantin I; Brower, Christopher S et al. (2016) Analyzing N-terminal Arginylation through the Use of Peptide Arrays and Degradation Assays. J Biol Chem 291:20976-20992
Liu, Yu-Jiao; Liu, Chao; Chang, ZeNan et al. (2016) Degradation of the Separase-cleaved Rec8, a Meiotic Cohesin Subunit, by the N-end Rule Pathway. J Biol Chem 291:7426-38
Wadas, Brandon; Borjigin, Jimo; Huang, Zheping et al. (2016) Degradation of Serotonin N-Acetyltransferase, a Circadian Regulator, by the N-end Rule Pathway. J Biol Chem 291:17178-96
Piatkov, Konstantin I; Vu, Tri T M; Hwang, Cheol-Sang et al. (2015) Formyl-methionine as a degradation signal at the N-termini of bacterial proteins. Microb Cell 2:376-393
Park, Sang-Eun; Kim, Jeong-Mok; Seok, Ok-Hee et al. (2015) Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway. Science 347:1249-1252
Varshavsky, Alexander (2014) Discovery of the biology of the ubiquitin system. JAMA 311:1969-70

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