# The regulation dephosphorylated-CoA-capped RNA and innate immunity by MESH1

> **NIH NIH R21** · DUKE UNIVERSITY · 2021 · $239,637

## Abstract

The intracellular innate immune response is triggered by the recognition of specific
pathogen-associated molecular patterns (PAMPs) of host cells to restrict and remove these
foreign species. RNA PAMPs often come from viruses, but can also come from cellular RNAs
that are improperly capped or have other foreign RNA features, including the presence or
absence of specific RNA modifications. Without pathogens, innate immunity can be also
activated under a diverse set of stress conditions (e.g., ischemia reperfusion and nutrient
deprivation) with significant impact on the tissue injury and regeneration. However, the
underlying mechanisms remains largely unknown. Here, we propose to investigate the role of a
stress-induced protein MESH1 to trigger innate immunity by regulating the levels of 3'-
dephosphorylated-CoA (dpCoA) and dpCoA-capped RNAs. MESH1 is a metazoan homologue
of the bacterial (p)ppGpp hydrolase SpoT that regulates bacterial stringent response triggered
by various nutrient deprivations and stresses. Because neither a homologue of the (p)ppGpp
synthetase nor (p)ppGpp itself has been found in metazoa, the substrates and functions of
MESH1 remain unknown. We have found that MESH1 is a CoA phosphatase which is induced
by ischemia-reperfusion and nutrient deprivations. Over-expression of MESH1 dramatically
increases the level of dpCoA and triggers dramatic induction of the interferons and inflammatory
cytokines. Therefore, we hypothesize that the elevated dpCoA upon MESH1 induction results in
the appearance of dpCoA-capped RNA that is sensed as foreign RNA by RNA-sensing
pathways of innate immunity. We will test this hypothesis in two specific aims. First, we will
characterize the enzymatic and functional activities of MESH1 as the first mammalian CoA
phosphatase and its regulation of dpCoA and CoA levels under various MESH1-inducing stress
conditions. Next, we will employ thio-reactive chemistry to capture and sequence dpCoA-
capped RNA species to identify functional or sequence enrichment. In addition, we will define
the effects of dpCoA cap on the translation, stability and other function of the RNA. Finally, we
will determine the functional role of dpCoA-capped mRNA in triggering the RNA-sensing
pathways of the innate immune response upon MESH1 induction. Together, the completion of
the proposed experiments will elucidate the novel enzymatic activities of CoA phosphatase in
regulating the levels of the dpCoA and dpCoA-RNA. These knowledge will enhance our
understanding the aberrant activation of innate immunity under various stress conditions in
various human diseases.

## Key facts

- **NIH application ID:** 10111461
- **Project number:** 5R21AI149205-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Jen-Tsan Ashley Chi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $239,637
- **Award type:** 5
- **Project period:** 2020-02-19 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111461

## Citation

> US National Institutes of Health, RePORTER application 10111461, The regulation dephosphorylated-CoA-capped RNA and innate immunity by MESH1 (5R21AI149205-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10111461. Licensed CC0.

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