PACT prevents aberrant activation of PKR by endogenous dsRNA without sequestration

The innate immune sensor PKR for double-stranded RNA (dsRNA) is critical for antiviral defense, but its aberrant activation by cellular dsRNA is linked to various diseases. The dsRNA-binding protein PACT plays a critical yet controversial role in this pathway. We show that PACT directly suppresses PKR activation by endogenous dsRNA ligands, such as inverted-repeat Alu RNAs, which robustly activate PKR in the absence of PACT. Instead of competing for dsRNA binding, PACT prevents PKR from scanning along dsRNA-a necessary step for PKR molecules to encounter and phosphorylate each other for activation. While PKR favors longer dsRNA for increased co-occupancy and scanning-mediated activation, longer dsRNA is also more susceptible to PACT-mediated regulation due to increased PACT-PKR co-occupancy. Unlike viral inhibitors that constitutively suppress PKR, this RNA-dependent mechanism allows PACT to fine-tune PKR activation based on dsRNA length and quantity, ensuring self-tolerance without sequestering most cellular dsRNA.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2025-04-08
DOI
https://doi.org/10.1038/s41467-025-58433-x
Citations
12
Primary Topic
RNA regulation and disease
Type
article
Field-Weighted Citation Impact
9.67

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

PACT prevents aberrant activation of PKR by endogenous dsRNA without sequestration

James J. Chou, Patrick Zhuang, Ilana Buchumenski, Matthew Meyerson et al.
12 citations
Nature Communications
RNA regulation and disease
9.67
article

PACT prevents aberrant activation of PKR by endogenous dsRNA without sequestration

James J. Chou, Patrick Zhuang, Ilana Buchumenski, Matthew Meyerson, Sua Myong, Tao Zou, Erez Y. Levanon, Jihee Hwang, Alyssa R. Fishbein, Diego Capcha-Rodriguez, Linlin Zhao, Sun Hur, Sadeem Ahmad, Aaron Orgel, Anton Davydenko, Xi Wang
article en
12 citations

Abstract

The innate immune sensor PKR for double-stranded RNA (dsRNA) is critical for antiviral defense, but its aberrant activation by cellular dsRNA is linked to various diseases. The dsRNA-binding protein PACT plays a critical yet controversial role in this pathway. We show that PACT directly suppresses PKR activation by endogenous dsRNA ligands, such as inverted-repeat Alu RNAs, which robustly activate PKR in the absence of PACT. Instead of competing for dsRNA binding, PACT prevents PKR from scanning along dsRNA-a necessary step for PKR molecules to encounter and phosphorylate each other for activation. While PKR favors longer dsRNA for increased co-occupancy and scanning-mediated activation, longer dsRNA is also more susceptible to PACT-mediated regulation due to increased PACT-PKR co-occupancy. Unlike viral inhibitors that constitutively suppress PKR, this RNA-dependent mechanism allows PACT to fine-tune PKR activation based on dsRNA length and quantity, ensuring self-tolerance without sequestering most cellular dsRNA.

Nature CommunicationsVol. 16(1)
Broad Institute (US), Tongji University (CN), Boston Children's Hospital (US), Howard Hughes Medical Institute (US), Harvard University (US), Bar-Ilan University (IL), Shanghai Institute of Organic Chemistry (CN), Dana-Farber Cancer Institute (US), Shanghai Tenth People's Hospital (CN)
Howard Hughes Medical Institute, Dana-Farber Cancer Institute, National Institutes of Health
Good health and well-being
Openalex Percentile: Top 2%
RNA regulation and disease
9.67
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.