[R21] MESH1 Regulates RNA Sensing Through Nucleotide Metabolism
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-04-30
Importo max: 237.831 EUR
Paese: US
Descrizione
Project Abstract
Proper recognition and disposal of aberrant RNA is essential for maintaining immune tolerance while
enabling appropriate antiviral defense. This process is tightly regulated by RNA decay enzymes such as the
5′→3′ exonuclease XRN1, whose activity prevents the accumulation of immunostimulatory RNA species that
can aberrantly activate RNA-sensing pathways like RIG-I and MDA5. Recent findings have uncovered an
unexpected role for the cytosolic enzyme MESH1 in regulating nucleotide metabolism and immune responses
to RNA. Originally identified as a metazoan homolog of the bacterial SpoT, MESH1 has been shown by us to
degrade NADPH and promote ferroptosis. Our preliminary data now identify 3′-phosphoadenosine 5′-
phosphate (PAP) as a novel, physiologically relevant substrate for MESH1. Furthermore, MESH1-deficient
macrophages exhibit an exaggerated response to immunostimulatory RNA. One probable explanation is that
PAP, a byproduct of cellular sulfation reactions, inhibits the XRN1, leading to the accumulation of
immunostimulatory RNAs that aberrantly trigger antiviral signaling. We hypothesize that MESH1 is a critical
PAP phosphatase that protects cells from PAP-induced dysregulation of RNA decay and inappropriate immune
activation. To test this, we propose two aims: In Aim 1, we will biochemically and structurally define the PAP
phosphatase activity of MESH1, including enzymatic kinetics, lithium sensitivity, and co-crystal structures with
PAP. We will also compare MESH1 with BPNT1, the Golgi-associated, lithium-sensitive PAP phosphatase, to
evaluate their relative capacities to regulate PAP levels in cellular compartments relevant to innate immune
sensing. In Aim 2, we will assess how MESH1 and PAP metabolism influence the innate immune response to
RNA-based danger signals, including viral infection and synthetic RNA ligands, using genetically modified
cells. The work is highly innovative, revealing a previously unrecognized regulatory axis between nucleotide
catabolism and innate immunity by forging cooperation among investigators with expertise in MESH1, RNA
immunology, and virus-host interactions. The results will uncover a novel layer of immune control with broad
implications for infection, inflammation, and autoimmunity, and may ultimately reveal MESH1 as a therapeutic
target to enhance antiviral immunity.
Istituzione: DUKE UNIVERSITY
PI: Jen-Tsan Ashley Chi, Stacy Michelle Horner
Progetto: 1R21AI200131-01
Settori: National Institute of Allergy and Infectious Diseases
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