# The Role of TRIM6 and Ubiquitin in Influenza Virus-Induced Pathology

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2021 · $461,016

## Abstract

ABSTRACT. Influenza A virus (IAV) causes annual epidemics and dangerous pandemics involving millions of
cases of illness and deaths worldwide. The main cause of pathology from IAV is excessive inflammation,
therefore, the overarching goal of this proposal is to learn how mechanisms of inflammation can be
manipulated to promote disease tolerance to virus infection. Cytokine production, a chief contributor of
inflammation, is regulated at the post-translational level to balance between efficient antiviral responses and
damaging inflammation. A major molecular regulatory mechanism involves ubiquitination of signaling
components. The specific goal of this proposal is to identify mechanisms of regulation of inflammation by
the ubiquitin (Ub) system during IAV infection in vivo.
 We recently reported that the E3-Ub ligase, TRIM6, catalyzes the synthesis of unanchored poly-Ub chains,
which promote antiviral IFN-I responses. However, the role of TRIM6 in regulating other inflammatory
cytokines is not known. We generated TRIM6 knockout mice (Trim6-/-), which provides a unique tool to
identify novel immune pathways regulated by TRIM6 and unanchored Ub in vivo. Our preliminary data show
that Trim6-/- mice have fewer signs of pathology even though there are increased IAV titers at early time points
post-infection. We also found reduced expression levels of CXCL1, a well-known neutrophil chemo-attractant,
which correlated with reduced neutrophil infiltration to the lungs of IAV-infected Trim6-/- mice. We found that
TRIM6 and unanchored Ub form a complex with PI3K/AKT signaling components, and their phosphorylation is
impaired in Trim6-/- cells. Our data also suggest that TNFα produced by infected cells induces pathogenic
CXCL1 in bystander cells to recruit neutrophils. Neutrophils are known to be recruited to the lung during IAV
infection and can play both protective and detrimental roles. However, what factors drive neutrophils to cause
tissue damage during infection are not well-understood. Therefore, there is a gap in knowledge on the
mechanisms of regulation of neutrophil recruitment and their roles in the balance between protective
responses and pathogenic inflammation. Our hypothesis is that TRIM6 is activated by TNFα signaling and
promotes early CXCL1-mediated pathogenic inflammation, thereby inhibiting disease tolerance. In Aim 1, we
will determine the cellular source of TRIM6-induced CXCL1, and its role in neutrophil recruitment to the lungs,
during IAV infection. We will demonstrate the role of early CXCL1 production in pathology and whether TNFα
is involved in inducing TRIM6-mediated CXCL1. In Aim 2, we will determine the mechanism by which TRIM6
and Ub modulate the activation of PI3K-AKT for downstream signaling and how TRIM6 is activated during
infection. The outcomes include the identification of the cellular source of pathogenic CXCL1, and the
mechanism by which TRIM6 is activated for signaling. This information will guide the development of
th...

## Key facts

- **NIH application ID:** 10296160
- **Project number:** 1R01AI155466-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Ricardo Rajsbaum
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $461,016
- **Award type:** 1
- **Project period:** 2021-05-13 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296160

## Citation

> US National Institutes of Health, RePORTER application 10296160, The Role of TRIM6 and Ubiquitin in Influenza Virus-Induced Pathology (1R01AI155466-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10296160. Licensed CC0.

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