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MuRF1 mediated ubiquitination of M-line Titin

ABSTRACT: MuRF1 mediated ubiquitination of titin promotes autophagy machinery recruitment onto titin. Titin ubiquitination appears dynamically regulated by myofibrillar stretch via the unfolding of an NL linker sequence, leading to different ubiquitination patterns of the chain. This mechanism might be compromised in the titin SNP rs 200675195, a possible factor in cardiomyopathy.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Barbara Franke

LAB HEAD: Olga Mayans

PROVIDER: PXD015340 | Pride | 2021-06-23

REPOSITORIES: Pride

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			Action	DRS
	20180525_AK_Bruno_Manso_Titinfragment_Ubi_S1_WT.raw	Raw
	20180525_AK_Bruno_Manso_Titinfragment_Ubi_S2_WT.raw	Raw
	20180525_Titinfragment.zip	Other
	20180622_AK_Bruno_TitinFrag_HF2_WT_1.raw	Raw
	20180622_AK_Bruno_TitinFrag_HF2_WT_2.raw	Raw

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MuRF1 mediated ubiquitination of M-line Titin D24728V

Project description:MuRF1 mediated ubiquitination of titin promotes autophagy machinery recruitment onto titin. Titin ubiquitination appears dynamically regulated by myofibrillar stretch via the unfolding of an NL linker sequence, leading to different ubiquitination patterns of the chain. This mechanism might be compromised in the titin SNP rs 200675195, a possible factor in cardiomyopathy.

2021-06-23 | PXD015339 | Pride

Identification of the MuRF1 skeletal muscle ubiquitylome through quantitative proteomics

Project description:MuRF1 is a muscle-specific E3 ubiquitin ligase and component of the ubiquitin proteasome system. MuRF1 is transcriptionally upregulated under conditions that cause muscle loss, in both rodents and humans, and is a recognized marker of muscle atrophy. In this study, we used in vivo electroporation to determine if MuRF1 overexpression alone can cause muscle atrophy and, in combination with ubiquitin proteomics, identify the endogenous MuRF1 substrates in skeletal muscle. Tibialis anterior (TA) muscles were transfected with an untagged MuRF1 plasmid or control plasmid for 14 days. A total of 963 ubiquitination sites, corresponding to 250 proteins, were quantified from the TA muscle. Statistical analysis revealed that the overexpression of MuRF1 resulted in significant upregulation of 153 ubiquitination sites on 45 proteins and significant downregulation of 16 sites on 11 proteins. Substrates of MuRF1 include contractile and metabolic proteins, deubiquitinases, p62, and VCP. Moreover, MuRF1-mediated ubiquitination leads to destabilization and breakdown of the sarcomere and reveals a role for MuRF1 in the regulation of additional proteolytic pathways in skeletal muscle.

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Project description:Titin is a striated muscle-specific giant elastic protein and largely responsible for the generation of the diastolic force in the cardiac myocyte. Cardiac titin undergoes developmental changes in isoform expression during the course of cardiac development. At present, at least five size classes of titin isoforms (N2B and N2BA-A1, A2, N1, N2) have been identified using SDS agarose gel electrophoresis. The larger titin isoform N2BAs gradually decreased with ages, in contrast, the smaller titin isoform N2B increased in normal cardiomyocyte, and cardiac myocytes containing a higher proportion of the smaller titin isoform N2B have stronger passive tension than that with a lower proportion of the larger titin isoform N2BAs. Recently we found an autosomal dominant mutation which caused totally opposite cardiac titin isoform expression as compared to developmental stages. The larger total titin isoform N2BA increased in mutant rat cardiac myocytes with ages instead of the smaller cardiac titin isoform N2B. For the moment, mechanism of titin isoform switch is still unknown, therefore, the mutant rats will give us nevol sight to elucidate the titin splicing mechanism. Keywords: Titin isoforms, autosomal dominant mutation

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Cardiac Muscle Ring Finger-1 (MuRF1) and Transcriptional Regulation of Ischemia-Reperfusion Injury In Vivo

Project description:We previously identified a role for the muscle-specific ubiquitin ligase MuRF1 (Muscle Ring Finger-1) in cardiac ischemia-reperfusion (I/R) injury. We found that cardiomyocyte-specific (alphaMHC-) MuRF1 transgenic mice (MuRF1 Tg+) mice were significantly protected from I/R injury. As we discovered MuRF1’s regulation of other transcriptions factors, we sought to identify other ways in which MuRF1 was cardioprotective in I/R injury. In the present study, we first identified the regulation of MuRF1 expression by qPCR in a porcine model of I/R injury. MuRF1 mRNA significantly increased within 90 minutes of I/R injury. We next assayed MuRF1 Tg+ ventricular tissue after I/R reperfusion injury by microarray (44K transcripts) to identify how MuRF1 regulates the transcriptome. We identified 71 significantly altered genes having a >1.5-fold (p<0.01) in MuRF1 Tg+ and wildtype hearts challenged with I/R injury (or sham operation). Functional annotation of the top upregulated genes found enrichment for myogenesis, cell adhesion, and nucleic acid metabolism. TRANSFAC analysis of MuRF1 Tg+ significant genes identified enrichment for genes (30-53%) with promoter regions recognized by the transcription factors MAZ, PIT1, VMW65, and BACH2. The transcription factor MAZ binds muscle creatine kinase (MCK) promoter in skeletal and cardiac myocytes, known most for its regulation of myogenin and MEF2C in cardiomyocytes. While the role of PIT1 and BACH2 in adult cardiomyocytes is not clear, VMW65 is a powerful transactivator with functions in chromatin remodeling. In neonatal cardiomycoyte I/R injury, VMW65 associates with HIF1alpha to upregulate cardioprotective VEGF, Glut-1, Glut-4, HSP70, and iNOS expression. These findings elucidate the MuRF1-specific regulation of genes in cardiac I/R injury that are associated with cardioprotection and may represent multiple additional direct or indirect mechanisms that MuRF1 regulates cardiomyocyte signaling.

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MuRF1 regulation of Fenofibrateâs induction of spontaneous cardiac hypertrophy in vivo.

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