Cooperative Role of PACT and ADAR1 in Preventing Aberrant PKR Activation by Self-Derived Double-Stranded RNA DOI Creative Commons
Lavanya Manjunath, Gisselle Santiago, Pedro Ortega

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 27, 2024

ABSTRACT Double-stranded RNAs (dsRNAs) produced during viral infections are recognized by the innate immune sensor protein kinase R (PKR), triggering a host translation shutoff that inhibits replication and propagation. Given harmful effects of uncontrolled PKR activation, cells must tightly regulate to ensure its activation occurs only in response infections, not endogenous dsRNAs. Here, we use CRISPR-Translate, FACS-based genome-wide CRISPR-Cas9 knockout screening method exploits levels as readout identifies PACT key inhibitor infection. We find deficient for hyperactivate several different RNA viruses, raising question why need limit activity. Our results demonstrate cooperates with ADAR1 suppress from self-dsRNAs uninfected cells. The simultaneous deletion synthetic lethality, which can be fully rescued PKR-deficient propose both act essential barriers against PKR, creating threshold tolerable dsRNA without activating PKR-mediated shutdown cell death.

Язык: Английский

RNA editing in disease: mechanisms and therapeutic potential DOI Open Access

Kasra Honarmand Tamizkar,

Michael F. Jantsch

RNA, Год журнала: 2025, Номер unknown, С. rna.080331.124 - rna.080331.124

Опубликована: Янв. 2, 2025

Adenosine to inosine conversion by ADARs was first identified in the late eighties of previous century. As adenosines inosines can be easily detected sequencing cDNAs, where presence an reads out as a guanosine, analysis this type RNA-editing has become widespread. Consequently, several pipelines for detecting transcriptomes have available. Still, how interpret consequences and alterations editomes is matter debate. In particular, cause or consequence altered on disease development poorly understood. Similarly, absolute frequencies editing events single molecules, their longitudinal distribution, naturally occurring changes during development, different tissues, response physiological need explored. Lastly, while use site-directed treatment certain genetic diseases rapidly evolving, applicability technology still faces technical obstacles. review, we describe current state knowledge adenosine deamination-type RNA-editing, its involvement potential therapeutic. highlight open challenges questions that addressed.

Язык: Английский

Процитировано

1
Cooperative role of PACT and ADAR1 in preventing aberrant PKR activation by self-derived double-stranded RNA DOI Creative Commons
Lavanya Manjunath, Gisselle Santiago, Pedro Ortega

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 5, 2025

Язык: Английский

Процитировано

1
Nuclear Retention and Rna Editing Suppress the Recognition of Undegraded Intron Lariats as Non-Self DOI
Keonyong Lee, Jayoung Ku,

Soo Young Park

и другие.

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Zα and Zβ Localize ADAR1 to Flipons That Modulate Innate Immunity, Alternative Splicing, and Nonsynonymous RNA Editing DOI Open Access
Alan Herbert, Oleksandr Cherednichenko, Terry P. Lybrand

и другие.

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(6), С. 2422 - 2422

Опубликована: Март 7, 2025

The double-stranded RNA editing enzyme ADAR1 connects two forms of genetic programming, one based on codons and the other flipons. recodes in pre-mRNA by deaminating adenosine to form inosine, which is translated as guanosine. also plays essential roles immune defense against viruses cancers recognizing left-handed Z-DNA Z-RNA (collectively called ZNA). Here, we review various aspects biology, starting with progressing has major isoforms, p110 protein lacking p150 Zα domain that binds ZNAs high affinity. isoform induced interferon targets ALU inverted repeats, a class endogenous retroelement promotes their transcription retrotransposition incorporating Z-flipons encode G-flipons G-quadruplexes (GQ). Both include Zβ related but does not bind ZNAs. Here report strong evidence GQ are formed co-transcriptionally repeats within R-loops. By binding GQ, suppresses ALU-mediated alternative splicing, generates most reported nonsynonymous edits R-loop resolution. recognition nucleic acid conformations programming flipons encoding information codons. findings suggest into editmers might improve therapeutic efficacy ADAR1.

Язык: Английский

Процитировано

0
Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy DOI Creative Commons

Z.C. Chen,

Rayk Behrendt,

Lennart Wild

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Март 19, 2025

Abstract Nucleic acids from both self- and non-self-sources act as vital danger signals that trigger immune responses. Critical illnesses such acute respiratory distress syndrome, sepsis, trauma ischemia lead to the aberrant cytosolic accumulation massive release of nucleic are detected by antiviral innate receptors in endosome or cytosol. Activation for deoxyribonucleic ribonucleic triggers inflammation, a major contributor morbidity mortality critically ill patients. In past decade, there has been growing recognition therapeutic potential targeting acid sensing critical care. This review summarizes current knowledge ischemia. Given extensive research on common pathological conditions like cancer, autoimmune disorders, metabolic disorders aging, we provide comprehensive summary beyond illness offer insights may inform its role conditions. Additionally, discuss strategies specifically target sensing. By examining sources, sensor activation function, well impact regulating these pathways across various diseases, highlight driving illness.

Язык: Английский

Процитировано

0
ADAR1 p150 prevents HSV-1 from triggering PKR/eIF2α-mediated translational arrest and is required for efficient viral replication DOI Creative Commons

Adwait Parchure,

Mia Cesarec,

Antonija Braut

и другие.

PLoS Pathogens, Год журнала: 2025, Номер 21(4), С. e1012452 - e1012452

Опубликована: Апрель 8, 2025

Adenosine deaminase acting on dsRNA 1 (ADAR1) catalyzes the deamination of adenosines to inosines in double-stranded RNAs (dsRNA) and regulates innate immunity by preventing hyperactivation cytosolic sensors such as MDA5, PKR or ZBP1. ADAR1 has been shown exert pro- antiviral, editing-dependent editing-independent functions viral infections, but little is known about its function herpesvirus replication. We now demonstrate that herpes simplex virus (HSV-1) hyperactivates absence ADAR1, resulting eIF2α mediated translational arrest reduced Silencing inhibition downstream effectors (ICP34.5) pharmacological (ISRIB) inhibitors rescues replication ADAR1-deficient cells. Upon infection, p150 interacts with prevents hyperactivation. Our findings an important proviral factor raises activation threshold for immunity.

Язык: Английский

Процитировано

0
Leveraging genetics to understand ADAR1-mediated RNA editing in health and disease DOI
Jin Billy Li, Carl R. Walkley

Nature Reviews Genetics, Год журнала: 2025, Номер unknown

Опубликована: Апрель 14, 2025

Язык: Английский

Процитировано

0
A-to-I RNA Editing and Hematopoiesis DOI Creative Commons
Zhen Liang, Carl R. Walkley, Jacki Heraud-Farlow

и другие.

Experimental Hematology, Год журнала: 2024, Номер 139, С. 104621 - 104621

Опубликована: Авг. 25, 2024

Adenosine-to-inosine (A-to-I) RNA editing plays essential roles in modulating normal development and homeostasis. This process is catalyzed by adenosine deaminase acting on (ADAR) family proteins. The most well-understood biological processes modulated A-to-I are innate immunity neurological development, attributed to ADAR1 ADAR2, respectively. also critical regulating hematopoiesis. review will focus the role of ADAR enzymes, particularly ADAR1, during hematopoiesis humans mice. Furthermore, we discuss Adar1 mouse models that have been developed understand contribution its immune pathways.

Язык: Английский

Процитировано

2
Distinct interactomes of ADAR1 nuclear and cytoplasmic protein isoforms and their responses to interferon induction DOI Creative Commons
Dragana Vukić, Anna Cherian, Salla Keskitalo

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 30, 2024

Abstract The RNA editing enzyme adenosine deaminase acting on 1 (ADAR1) is essential for correct functioning of innate immune responses. ADAR1p110 isoform mainly nuclear and ADAR1p150, which interferon (IFN) inducible, predominately cytoplasmic. Using three different methods – co-immunoprecipitation (co-IP) endogenous ADAR1, Strep-tag co-IP BioID with individual ADAR1 isoforms a comprehensive interactome was generated during both homeostasis the IFN response. Both known novel interactors as well regulators were identified. Nuclear proteins detected stable isoforms. In contrast, identified distinct protein networks each isoform, components observed cytoplasmic cellular condensates ADAR1p150. RNase A digestion distinguished between distal proximal interactors, did double-stranded (dsRNA)-binding mutant demonstrated importance dsRNA binding interactions. treatment not affect core interactomes but resulted in interactions, majority are interactions retained after treatment. Short high molecular weight poly(I:C) response dsRNA-binding-dependent changes network association ADAR1p150 some antiviral stress granules.

Язык: Английский

Процитировано

2
Cooperative Role of PACT and ADAR1 in Preventing Aberrant PKR Activation by Self-Derived Double-Stranded RNA DOI Creative Commons
Lavanya Manjunath, Gisselle Santiago, Pedro Ortega

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 27, 2024

ABSTRACT Double-stranded RNAs (dsRNAs) produced during viral infections are recognized by the innate immune sensor protein kinase R (PKR), triggering a host translation shutoff that inhibits replication and propagation. Given harmful effects of uncontrolled PKR activation, cells must tightly regulate to ensure its activation occurs only in response infections, not endogenous dsRNAs. Here, we use CRISPR-Translate, FACS-based genome-wide CRISPR-Cas9 knockout screening method exploits levels as readout identifies PACT key inhibitor infection. We find deficient for hyperactivate several different RNA viruses, raising question why need limit activity. Our results demonstrate cooperates with ADAR1 suppress from self-dsRNAs uninfected cells. The simultaneous deletion synthetic lethality, which can be fully rescued PKR-deficient propose both act essential barriers against PKR, creating threshold tolerable dsRNA without activating PKR-mediated shutdown cell death.

Язык: Английский

Процитировано

0