Evidence map›Paper›PMID 26383969›Full record

ArticleCirculation research2015

COP9 signalosome controls the degradation of cytosolic misfolded proteins and protects against cardiac proteotoxicity.

Huabo Su, Jie Li, Hanming Zhang, Wenxia Ma, Ning Wei, Jinbao Liu, Xuejun Wang

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
29citing papers in PubMed, 1 pooled it
1.1field-weighted citation impact, top 23% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

29 citing papers in PubMed, 1 synthesis or guideline pooled it, 44 citations in OpenAlex.

  1. Pooled it
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  6. A window into intracellular events in myositis through subcellular proteomics.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2025
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  13. International journal of biological sciences · 2022
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

7 authors at 2 institutions in 2 countries.

Huabo SuFrom the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.).
Jie LiFrom the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.).
Hanming ZhangFrom the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.).
Wenxia MaFrom the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.).
Ning WeiFrom the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.).
Jinbao LiuFrom the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.). xuejun.wang@usd.edu jliu@gzhmu.edu.cn.
Xuejun WangFrom the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.). xuejun.wang@usd.edu jliu@gzhmu.edu.cn.
Yale University · USAugusta University · US

Funding

Ubiquitin receptors and cardiac proteotoxicityR01HL072166 · NHLBI · UNIVERSITY OF SOUTH DAKOTA · PI WANG, XUEJUN · 2003 to 2023
$6.9M
The COP9 SIgnalosome in the HeartR01HL085629 · NHLBI · UNIVERSITY OF SOUTH DAKOTA · PI WANG, XUEJUN · 2006 to 2019
$4.7M
Neddylation and cardiac protein quality controlR01HL124248 · NHLBI · AUGUSTA UNIVERSITY · PI SU, HUABO · 2014 to 2024
$4.1M
NHLBI NIH HHS R01 HL072166NHLBI NIH HHS R01HL072166NHLBI NIH HHS R01 HL085629NHLBI NIH HHS R01HL085629NHLBI NIH HHS R01 HL124248NHLBI NIH HHS R01HL124248
6 · The paper itself

Abstract

rationaleImpaired degradation of misfolded proteins is associated with a large subset of heart diseases. Misfolded proteins are degraded primarily by the ubiquitin-proteasome system, but the ubiquitin ligases responsible for the degradation remain largely unidentified. The cullin deneddylation activity of the COP9 signalosome (CSN) requires all 8 CSN subunits (CSN1 through CSN8) and regulates cullin-RING ligases, thereby controlling ubiquitination of a large number of proteins; however, neither CSN nor cullin-RING ligases is known to regulate the degradation of cytosolic misfolded proteins.

objectiveWe sought to investigate the role of CSN8/CSN in misfolded protein degradation and cardiac proteinopathy. METHODS AND

resultsCardiac CSN8 knockout causes mouse premature death; hence, CSN8 hypomorphism (CSN8(hypo)) mice were used. Myocardial neddylated forms of cullins were markedly increased, and myocardial capacity of degrading a surrogate misfolded protein was significantly reduced by CSN8 hypomorphism. When introduced into proteinopathic mice in which a bona fide misfolded protein R120G missense mutation of αβ-crystallin (CryAB(R120G)) is overexpressed in the heart, CSN8 hypomorphism aggravated CryAB(R120G)-induced restrictive cardiomyopathy and shortened the lifespan of CryAB(R120G) mice, which was associated with augmented accumulation of protein aggregates, increased neddylated proteins, and reduced levels of total ubiquitinated proteins and LC3-II in the heart. In cultured cardiomyocytes, both CSN8 knockdown and cullin-RING ligase inactivation suppressed the ubiquitination and degradation of CryAB(R120G) but not native CryAB, resulting in accumulation of protein aggregates and exacerbation of CryAB(R120G) cytotoxicity.

conclusions(1) CSN8/CSN promotes the ubiquitination and degradation of misfolded proteins and protects against cardiac proteotoxicity, and (2) cullin-RING ligases participate in degradation of cytosolic misfolded proteins.

Indexed as

Signal Transductionalpha-Crystallin B ChainAnimalsAnimals, NewbornAutophagyCarrier ProteinsCells, CulturedCOP9 Signalosome ComplexCullin ProteinsCytosolFemaleGenotypeHeart DiseasesHeart VentriclesMaleMice, Inbred C57BLalpha-Crystallin B ChainCarrier ProteinsCOP9 Signalosome ComplexCops8 protein, mouseCryab protein, mouseCullin ProteinsMap1lc3b protein, mouseMicrotubule-Associated ProteinsautophagyCOP9 signalosomeCops8desmin-related cardiomyopathyproteasomeubiquitin

Identifiers

PMID26383969
PMCPMC4636927
OpenAlexW2198153787

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.