# Superchanneling, Regulation of Caspases, and Site-Specific Control of RNA

> **NIH NIH R01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2024 · $484,500

## Abstract

Project Summary/Abstract
 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 41st 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, in particular, specific unmodified Nt-residues
of protein substrates.
 This GM031530 renewal application stems from our unpublished studies over the last ~2 years, and
focuses on new, previously unexplored aspects of the Arg/N-degron pathway. Specific proposed studies
address a coupling between a C-degron and stability of a protein’s mRNA, the new phenomenon of
superchanneling in targeting specific degrons, and a functional (as well as mechanistic) link between human
caspases and the Arg/N-degron pathway. Our studies of this universally present proteolytic system will
contribute to advances in fundamental biology and may also lead to therapies for specific human diseases.

## Key facts

- **NIH application ID:** 10731471
- **Project number:** 2R01GM031530-42
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** ALEXANDER J VARSHAVSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $484,500
- **Award type:** 2
- **Project period:** 1992-07-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10731471

## Citation

> US National Institutes of Health, RePORTER application 10731471, Superchanneling, Regulation of Caspases, and Site-Specific Control of RNA (2R01GM031530-42). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10731471. Licensed CC0.

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