ADAR and hnRNPC Deficiency Synergize in Activating Endogenous dsRNA-Induced Type I IFN Responses

Authors

Anna-Maria Herzner
Zia Khan
Eric L Van Nostrand
Sara Chan
Trinna Cuellar
Ronald Chen
Ximo Pechuan-Jorge
Laszlo Komuves
Margaret Solon
Zora Modrusan
Benjamin Haley
Gene W Yeo
Timothy W Behrens
Matthew L Albert

Publication Date

9-6-2021

Journal

Journal of Experimental Medicine

DOI

10.1084/jem.20201833

PMID

34297039

PMCID

PMC8313407

PubMedCentral® Posted Date

7-23-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Adenosine Deaminase, Alu Elements, CRISPR-Cas Systems, Cytosol, Heterogeneous-Nuclear Ribonucleoprotein Group C, Humans, Interferon Type I, Interferon-Induced Helicase, IFIH1, Introns, MCF-7 Cells, Membrane Proteins, RNA Editing, RNA, Double-Stranded, RNA-Binding Proteins, THP-1 Cells

Abstract

Cytosolic double-stranded RNA (dsRNA) initiates type I IFN responses. Endogenous retroelements, notably Alu elements, constitute a source of dsRNA. Adenosine-to-inosine (A-to-I) editing by ADAR induces mismatches in dsRNA and prevents recognition by MDA5 and autoinflammation. To identify additional endogenous dsRNA checkpoints, we conducted a candidate screen in THP-1 monocytes and found that hnRNPC and ADAR deficiency resulted in synergistic induction of MDA5-dependent IFN responses. RNA-seq analysis demonstrated dysregulation of Alu-containing introns in hnRNPC-deficient cells via utilization of unmasked cryptic splice sites, including introns containing ADAR-dependent A-to-I editing clusters. These putative MDA5 ligands showed reduced editing in the absence of ADAR, providing a plausible mechanism for the combined effects of hnRNPC and ADAR. This study contributes to our understanding of the control of repetitive element-induced autoinflammation and suggests that patients with hnRNPC-mutated tumors might maximally benefit from ADAR inhibition-based immunotherapy.

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