# The Role of TRIM23 in Autophagy Mediated Antiviral Defenses

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $462,633

## Abstract

PROJECT SUMMARY
 Autophagy, the process by which cells dispose of cellular contents, has been
increasingly appreciated as an important pathway in antiviral host defenses. Intriguingly, recent
studies demonstrated that autophagy and the antiviral type I IFN response are intricately
connected, and several molecules known to play key roles in IFN-mediated immunity are also
important regulators of autophagy. Among these molecules with dual roles in autophagy and
IFN-mediated immunity are several TRIM (tripartite motif) protein family members. However,
whereas the molecular mechanisms by which TRIM proteins act as antiviral restriction factors or
regulate IFN responses have been well characterized, our knowledge about the role of TRIM
proteins in autophagy in response to viral infection is still rudimentary.
 The proposed study builds on a recent discovery by the Gack laboratory that identified
TRIM23 as a critical regulator of autophagy-mediated host defense against a broad range of
viruses. TRIM23 interacts with and activates the innate immune molecule TBK1, promoting
TBK1-mediated phosphorylation of the selective autophagy receptor p62, which ultimately
triggers viral clearance and host resistance. Mechanistically, the N-terminal RING E3 ligase of
TRIM23 induces atypical non-degradative K27-linked auto-ubiquitination of the C-terminal ARF
GTPase domain, which is unique to TRIM23. ARF ubiquitination results in enhanced activity of
TRIM23 to hydrolyze GTP, activate TBK1, and mediate virus resistance. TRIM23 depletion or
gene-targeting in various cell types showed that TRIM23-mediated autophagy confers antiviral
activity against several viruses including HSV-1.
 Using molecular, biochemical, cell biological and structural approaches combined with
virus infection studies, we will define in precise detail how TRIM23 mediates autophagy during
viral infection. This study will yield insight into the mechanisms of TRIM23 activation by
upstream regulators during viral infection (Aim 1). We will further determine the molecular
details of how TRIM23 activates TBK1 and the role the enzymatic activities of TRIM23 – E3
ligase and GTPase – play in TBK1 activation. Finally, we will determine the physiological
relevance of TRIM23 for antiviral host resistance and viral pathogenesis using in vitro cell
culture systems and infection studies in TRIM23 knockout mice (Aim 2). Our studies will provide
a molecular understanding of a key pathway in the autophagy-mediated host defense, which
may guide the rational design of new antivirals.

## Key facts

- **NIH application ID:** 10052408
- **Project number:** 1R01AI148534-01A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Michaela Ulrike Gack
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $462,633
- **Award type:** 1
- **Project period:** 2020-06-01 → 2020-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052408

## Citation

> US National Institutes of Health, RePORTER application 10052408, The Role of TRIM23 in Autophagy Mediated Antiviral Defenses (1R01AI148534-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10052408. Licensed CC0.

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