PACT prevents aberrant activation of PKR by endogenous dsRNA without sequestration

Sadeem Ahmad, Tao Zou, Jihee Hwang, Linlin Zhao, Xi Wang, Anton Davydenko, Ilana Buchumenski, Patrick Zhuang, Alyssa R. Fishbein, Diego Capcha-Rodriguez, Aaron Orgel, Erez Y. Levanon, Sua Myong, James Chou (), Matthew Meyerson () and Sun Hur ()
Additional contact information
Sadeem Ahmad: Boston Children’s Hospital
Tao Zou: Dana-Farber Cancer Institute
Jihee Hwang: Harvard Medical School
Linlin Zhao: Harvard Medical School
Xi Wang: Boston Children’s Hospital
Anton Davydenko: Boston Children’s Hospital
Ilana Buchumenski: Bar-Ilan University
Patrick Zhuang: Dana-Farber Cancer Institute
Alyssa R. Fishbein: Dana-Farber Cancer Institute
Diego Capcha-Rodriguez: Dana-Farber Cancer Institute
Aaron Orgel: Dana-Farber Cancer Institute
Erez Y. Levanon: Bar-Ilan University
Sua Myong: Harvard Medical School
James Chou: Harvard Medical School
Matthew Meyerson: Dana-Farber Cancer Institute
Sun Hur: Boston Children’s Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-58433-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58433-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-58433-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().