Regulation of ADP-ribosyltransferase activity by ART domain dimerization in PARP15 DOI Open Access
Carmen Ebenwaldner,

Antonio Ginés García Saura,

Simon Ekström

и другие.

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

Опубликована: Апрель 4, 2024

Abstract PARP15 is a mono-ADP-ribosyltransferase with unknown functions. Its evolutionary relationship PARP14 suggests roles in antiviral defense; its ability to modify RNA and localization stress granules point functions the regulation of translation. also modifies itself other proteins using ADP-ribosyltransferase (ART) domain contains two macrodomains predicted bind ADP-ribosyl on targets. We used biochemical biophysical analysis study how activity regulated. Here we show that catalytic dimerizes mid-nanomolar affinity, forming same dimer interface solution had already been captured by X-ray crystallography domain. Furthermore, formation dimers prerequisite for monomeric mutant variants were catalytically inactive. Our findings suggest regulatory mechanism which dimerization linked either target engagement or placement residue, rather than NAD+ co-substrate binding, protomers operate independent one another. Together, our results uncover novel PARP family enzyme, might inspire new avenues pharmacological intervention.

Язык: Английский

Body‐wide genetic deficiency of poly(ADP‐ribose) polymerase 14 sensitizes mice to colitis DOI Creative Commons
Madhukar Vedantham, Lauri Polari, Anbu Poosakkannu

и другие.

The FASEB Journal, Год журнала: 2024, Номер 38(13)

Опубликована: Июль 5, 2024

Abstract Inflammatory bowel disease (IBD) is a chronic of the gastrointestinal tract affecting millions people. Here, we investigated expression and functions poly(ADP‐ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, with IBD patient cohort as well two mouse colitis models, that is, IBD‐mimicking oral dextran sulfate sodium (DSS) exposure Salmonella infection. Parp14 was expressed human colon by cells lamina propria, but, particular, epithelial granular staining pattern cytosol. The same evidenced both models. Parp14‐deficiency caused increased rectal bleeding stronger erosion, Goblet cell loss, infiltration DSS‐exposed mice. absence did not affect bacterial microbiota. Also, leukocyte populations Parp14‐deficient mice were normal. In contrast, bulk tissue RNA‐Seq demonstrated transcriptomes dominated abnormalities inflammation infection responses prior after DSS exposure. Overall, data indicate has role maintenance barrier integrity. prognostic predictive biomarker potential merits further investigation.

Язык: Английский

Процитировано

2
A PARP14/TARG1-Regulated RACK1 MARylation Cycle Drives Stress Granule Dynamics in Ovarian Cancer Cells DOI Creative Commons
Sridevi Challa, Tulip Nandu, Hyung Bum Kim

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 14, 2023

Abstract Mono(ADP-ribosyl)ation (MARylation) is emerging as a critical regulator of ribosome function and translation. Herein, we demonstrate that RACK1, an integral component the ribosome, MARylated on three acidic residues by mono(ADP-ribosyl) transferase (MART) PARP14 in ovarian cancer cells. MARylation RACK1 required for stress granule formation promotes colocalization granules with G3BP1, eIF3η, 40S ribosomal proteins. In parallel, observed reduced translation subset mRNAs, including those encoding key regulators (e.g., AKT). Treatment inhibitor or mutation sites blocks these outcomes, well growth cells culture vivo. To re-set system after prolonged recovery, ADP-ribosyl hydrolase TARG1 deMARylates leading to dissociation restoration Collectively, our results therapeutically targetable pathway controls assembly disassembly Summary We have discovered druggable PARP14/TARG1-regulated mediates site- specific mono(ADP-ribosyl)ation protein. This disassembly, modulate

Язык: Английский

Процитировано

6
Mono-ADP-ribosylation, a MARylationmultifaced modification of protein, DNA and RNA: characterizations, functions and mechanisms DOI Creative Commons
Hao Wu, Anqi Lu,

Jiuzhi Yuan

и другие.

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Май 11, 2024

Abstract The functional alterations of proteins and nucleic acids mainly rely on their modifications. ADP-ribosylation is a NAD + -dependent modification and, in some cases, acids. This broadly categorized as Mono(ADP-ribosyl)ation (MARylation) or poly(ADP-ribosyl)ation (PARylation). MARylation catalyzed by mono(ADP-ribosyl) transferases (MARTs) more common cells the number MARTs much larger than poly(ADP-ribosyl) transferases. Unlike PARylation well-characterized, research at starting stage. However, growing evidence demonstrate cellular functions MARylation, supporting its potential roles human health diseases. In this review, we outlined MARylation-associated including MARTs, ADP-ribosyl hydrolyses ADP-ribose binding domains. We summarized up-to-date findings about onto newly identified substrates protein, DNA RNA, focused these reactions pathophysiological conditions well speculated mechanisms. Furthermore, new strategies detection current state inhibitors were discussed. also provided an outlook for future study, aiming to revealing unknown biological properties relevant mechanisms, establish novel therapeutic perspective

Язык: Английский

Процитировано

2
Single-cell and bulk RNA sequencing highlights the role of M1-like infiltrating macrophages in antibody-mediated rejection after kidney transplantation DOI Creative Commons

Qidan Pang,

Liang Chen,

Changyong An

и другие.

Heliyon, Год журнала: 2024, Номер 10(6), С. e27865 - e27865

Опубликована: Март 1, 2024

BackgroundAntibody-mediated rejection (ABMR) significantly affects transplanted kidney survival, yet the macrophage phenotype, ontogeny, and mechanisms in ABMR remain unclear.MethodMethod: We analyzed post-transplant sequencing clinical data from GEO ArrayExpress. Using dimensionality reduction clustering on scRNA-seq data, we identified subpopulations compared their infiltration non-rejection cases. Cibersort quantified these bulk samples. Cellchat, SCENIC, monocle2, monocle3 helped explore intercellular interactions, predict transcription factors, model cell subgroup differentiation. The Scissor method linked subgroups with transplant prognosis. Furthermore, hdWGCNA, nichnet, lasso regression key genes associated core factors prognosis-affecting differential macrophages, validated by external datasets.ResultsSix were five biopsies. M1-like infiltrating prevalent ABMR, correlated pathological injury severity. MIF was a primary signal macrophages. STAT1 regulated monocyte-to-M1-like transformation, impacting prognosis via IFNγ pathway. prognostic models built upstream downstream of effectively predicted survival. TLR4-STAT1-PARP9 axis may regulate pro-inflammatory phenotype identifying PARP9 as potential target for mitigating inflammation.ConclusionOur study delineates landscape post-kidney transplantation, underscoring detrimental impact macrophages pathology

Язык: Английский

Процитировано

1
Regulation of ADP-ribosyltransferase activity by ART domain dimerization in PARP15 DOI Open Access
Carmen Ebenwaldner,

Antonio Ginés García Saura,

Simon Ekström

и другие.

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

Опубликована: Апрель 4, 2024

Abstract PARP15 is a mono-ADP-ribosyltransferase with unknown functions. Its evolutionary relationship PARP14 suggests roles in antiviral defense; its ability to modify RNA and localization stress granules point functions the regulation of translation. also modifies itself other proteins using ADP-ribosyltransferase (ART) domain contains two macrodomains predicted bind ADP-ribosyl on targets. We used biochemical biophysical analysis study how activity regulated. Here we show that catalytic dimerizes mid-nanomolar affinity, forming same dimer interface solution had already been captured by X-ray crystallography domain. Furthermore, formation dimers prerequisite for monomeric mutant variants were catalytically inactive. Our findings suggest regulatory mechanism which dimerization linked either target engagement or placement residue, rather than NAD+ co-substrate binding, protomers operate independent one another. Together, our results uncover novel PARP family enzyme, might inspire new avenues pharmacological intervention.

Язык: Английский

Процитировано

1