# Negative regulation of innate immune signaling pathways by the selective autophagy receptor TAX1BP1

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2021 · $642,863

## Abstract

ABSTRACT
Innate immunity provides the first line of host defense in response to invading pathogens. Pattern recognition
receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs) in viruses and other pathogens.
RIG-I/MDA-5 are DExD/H box RNA helicases in the RIG-I-like receptor (RLR) pathway that detect double
stranded RNA viral genomes and activate the mitochondrial adaptor protein MAVS. The DNA sensor cGAS
detects double stranded DNA and activates STING, a transmembrane endoplasmic reticulum adaptor. Both
MAVS and STING activate canonical (IKKa and IKKb), and noncanonical IKK kinases (TBK1 and IKKi) to
activate transcription factors NF-kB and IRF3 respectively. Together, IRF3 and NF-kB regulate the expression
of type I interferon (IFN) and inflammatory genes that coordinate the innate response and initiate the adaptive
immune response against pathogens. The NLRP3 inflammasome also plays a critical role in inflammatory
responses by triggering caspase-1-mediated pro-IL-1b cleavage to yield the biologically active form of IL-
1b that drives inflammation and adaptive immunity. NLRP3 also induces a highly lytic form of inflammatory cell
death termed pyroptosis via cleavage of gasdermin-D to form plasma membrane pores. The RLR, cGAS-
STING and NLRP3 inflammasome pathways are potent inducers of inflammation that must be tightly regulated
to avert overexuberant inflammation and tissue damage. TAX1BP1 was first identified as an anti-apoptotic
protein that interacts with the zinc finger deubiquitinase A20/TNFAIP3. Our previous work has established that
TAX1BP1 restricts cytokine-induced NF-kB activation as well as RLR-induced type I IFN production and
apoptosis. TAX1BP1 functions as a selective autophagy receptor by recruiting ubiquitinated cargo to
developing autophagosomes via two LC3 interaction regions (LIRs). However, it remains unclear how
TAX1BP1 autophagy function is regulated and if TAX1BP1 inhibits other innate immune signaling pathways. In
preliminary studies we provide experimental evidence that TAX1BP1 is phosphorylated by both noncanonical
and canonical IKK kinases which controls both basal and virus-induced TAX1BP1 autophagic degradation
respectively. Using TAX1BP1-deficient macrophages we have demonstrated that TAX1BP1 is a novel inhibitor
of both cGAS-STING and NLRP3 pathways. Furthermore, MAVS protein aggregates accumulate in TAX1BP1-
deficient cells suggesting a potential aggrephagy function in the regulation of innate immune signaling. The
central hypothesis driving the proposed investigations is that TAX1BP1 inhibits RLR, cGAS-STING and NLRP3
pathways by autophagy-mediated clearance of signaling protein aggregates. We will test this hypothesis
experimentally with the following Specific Aims: (1) determine the role of TAX1BP1 phosphorylation in its
autophagy function, (2) determine the mechanisms of TAX1BP1 inhibition of the cGAS-STING pathway, and
(3) determine the mechanisms of TAX1BP1 inhibition of the NLRP3 pathway. Com...

## Key facts

- **NIH application ID:** 10276931
- **Project number:** 1R01AI162815-01
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** EDWARD W HARHAJ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $642,863
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10276931

## Citation

> US National Institutes of Health, RePORTER application 10276931, Negative regulation of innate immune signaling pathways by the selective autophagy receptor TAX1BP1 (1R01AI162815-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10276931. Licensed CC0.

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