# Mechanism and Function of ISG15

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $464,326

## Abstract

SUMMARY
 Human ISG15 is a ubiquitin-like protein (Ubl) that functions in innate immune responses, and it is
remarkable for possessing three distinct biochemical activities. As a ubiquitin-like modifier it is conjugated to
hundreds of cellular and viral proteins. The E1, E2, E3, and de-conjugating enzymes for ISG15 (Ube1L/Uba7,
UbcH8/Ube2L6, Herc5, and Usp18, respectively), are, like ISG15, induced at the transcriptional level by Type I
interferon (IFN-α/β) signaling. A second function of ISG15 is as an extracellular signaling protein. ISG15 is
released into the extracellular space from many cell types and signals to Natural Killer and T cells to secrete
IFN-γ, which plays a major role in the response to pathogen infections. The cell surface receptor for
extracellular SG15 is LFA-1, an immune cell-specific integrin. A third function of human ISG15 is that it
negatively regulates Type I IFN signaling, as revealed by the Type I interferonopathy that occurs in some
ISG15-deficient patients; this function of human ISG15 is not shared with mouse ISG15. A challenge in the
field is to understand how the activities of ISG15 are regulated and temporally controlled and which activities
are most closely associated with responses to specific pathogens, including Mycobacterium tuberculosis and
SARS-CoV-2. To further our understanding of ISG15 in innate immune responses to these and other
pathogens, this proposal will focus on the basis of substrate and lysine selectivity of the Herc5/Herc6 family of
ISG15 ligases, the ISG15-induced signaling pathway downstream of LFA-1 that leads to cytokine secretion,
and the mechanism by which ISG15 released into the extracellular space.

## Key facts

- **NIH application ID:** 10851708
- **Project number:** 5R01AI096090-14
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** JON HUIBREGTSE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $464,326
- **Award type:** 5
- **Project period:** 2011-05-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851708

## Citation

> US National Institutes of Health, RePORTER application 10851708, Mechanism and Function of ISG15 (5R01AI096090-14). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10851708. Licensed CC0.

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