Drebrin-like protein DBN-1 is a sarcomere component that stabilizes actin filaments during muscle contraction

Butkevich, Eugenia; Bodensiek, Kai; Fakhri, Nikta; Roden, Kerstin von; Schaap, Iwan A. T.; Majoul, Irina; Schmidt, Christoph F.; Klopfenstein, Dieter R.

doi:10.1038/ncomms8523

Cited by 17 publications

(40 citation statements)

References 59 publications

(64 reference statements)

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“…32,33) Specifically, polymerization/depolymerization of α-SMA is controlled by the actin depolymerizing factor (ADF)/cofilin family, which binds polymerized actin (Factin) and breaks it down into G-actin by depolymerization, thereby regulating the stability and function of α-SMA. 34) We found that C/EBPβ knockdown could reduce the protein expression of cofilin and FLNA, suggesting that the cofilin/FLNA signaling pathway may be a downstream effector of C/EBPβ during CF differentiation. C/EBPβ is an intronless gene that codes for the production of a single mRNA.…”

Section: Discussionmentioning

confidence: 70%

The Inflammatory Transcription Factor C/EBPβ Plays a Critical Role in Cardiac Fibroblast Differentiation and a Rat Model of Cardiac Fibrosis Induced by Autoimmune Myocarditis

Sun

Men

et al. 2018

Int. Heart J.

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The aim of the present study was to investigate the mechanisms of CCAAT/enhancer-binding protein β (C/ EBPβ) in cardiac myofibroblast (CMF) differentiation and in a rat model of cardiac fibrosis induced by experimental autoimmune myocarditis (EAM). In vitro studies performed in primary neonatal rat CMF revealed that silencing of C/EBPβ expression (via lentiviral mediated shRNA strategies) was sufficient to reduce C/EBPβ mRNA and protein levels as well as to decrease the expressions of actin cytoskeletal proteins, cofilin, and filamin A (FLNA). TGFβ increased IL-1β, IL-6 and TNF-a production in cardiac fibroblasts (CF), while C/EBPβ knockdown reduced the secretion of these inflammatory mediators. In vivo studies performed in rats exhibiting EAM revealed that lentiviralmediated silencing of C/EBPβ was sufficient to reduce the expression of C/EBPβ as well as inflammation and fibrosis in the hearts of EAM rats, when compared to controls. Echocardiography further revealed that C/EBPβ knockdown was sufficient to significantly improve cardiac dimensions and function in EAM rats. Immunohistochemical results showed that C/EBPβ knockdown attenuated the expression of C/EBPβ protein as well as the expressions of collagen I, collagen III, MMP-2, MMP-9, and α-SMA in heart tissue sections from rats in the EAM + Lenti-shC/EBPβ group. Strategies targeted at inhibiting C/EBPβ expression can be potentially exploited to regulate cofilin and FLNA expression, thereby regulating actin polymerization/depolymerization, cytoskeleton rearrangement, and CF differentiation into CMF and the production of inflammatory cytokines. C/EBPβ knock down reduces the degree of inflammation-mediated myocardial fibrosis in a rat model of EAM.

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Section: Discussionmentioning

confidence: 70%

The Inflammatory Transcription Factor C/EBPβ Plays a Critical Role in Cardiac Fibroblast Differentiation and a Rat Model of Cardiac Fibrosis Induced by Autoimmune Myocarditis

Sun

Men

et al. 2018

Int. Heart J.

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“…C. elegans DBN-1 is a multi-domain protein that contains an N-terminal ADF-H domain, three coiled-coils (3xCC), a proline-rich sequence and a C-terminal SH3 domain, of which the 3xCC domain of DBN-1 was shown to bind F-actin in vitro 29 . The ok925 mutation that truncates DBN-1 after two coiled-coils leads to a mild disorganization of actin filaments during body-wall muscle contraction 29 and affects vesicle scission during endocytosis in the intestine 27 . However, the remaining N-terminal part of DBN-1 in the ok925 mutant is sufficient to support its wild-type-like locomotion (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Transgenic strains were generated by microinjection 50 DBN-1. The reason for the generation of these antibodies was that the antibodies against fulllength DBN-1 described in 29 do not recognize the ADF-H domain of DBN-1.…”

Section: Transgene Generation and Crossingsmentioning

confidence: 99%

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Drebrin-like protein regulates body bending ofC. elegansvia suppression of NCA cation leak channels

Butkevich

Weist

Härtter

et al. 2019

Preprint

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Drebrin-like protein (DBN-1) in C. elegans is an adaptor protein that connects different cellular pathways to the actin cytoskeleton. Using a CRISPR-Cas9 system, we generated a new dbn-1 allele, which lacks 80% of C-terminal part of DBN-1. The mutant displays a striking hyper-bending locomotion phenotype and body posture with two times stronger curvature than wild type. We show by atomic force microscopy that the muscle tone of the mutant remains unaffected. Aiming to track down the cause of hyper-bending, we performed genetic epistasis experiments. We found that mutations in the Rho-specific guanine-nucleotide exchange factor (GEF) domain of UNC-73 (Trio), pan-neuronal expression of dominant negative RHO-1 and mutations in NCA (NALCN) cation leak channels all suppressed hyper-bending in the dbn-1 mutant. These data indicate that DBN-1 negatively regulates the activity of both NCA-1 and NCA-2 channels, opposing RHO-1 in the

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“…DBNL is an important player that mediates endocytosis and vesicle recycling 4,[9][10][11][12] . In addition, it regulates actin dynamics during formation of dorsal ruffles 5 and podosomes 13 as well as during sarcomere contraction 3 . A re-…”

Section: Introductionmentioning

confidence: 99%

Dimerization of human drebrin-like protein governs its biological activity

Ghosh

Enderlein

Butkevich

2019

Preprint

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AbstractDrebrin-like protein (DBNL) is a multidomain F-actin binding protein, which also interacts with other molecules within different intracellular pathways. Here, we present quantitative measurements on size and conformation of human DBNL. Using dual focus fluorescence correlation spectroscopy, we determined the hydrodynamic radius of DBNL monomer. Native gel electrophoresis and dual color fluorescence cross-correlation spectroscopy show that both endogenous and recombinant DBNL exist as dimer under physiological conditions. We demonstrate that C-terminal truncations of DBNL downstream of the coiled-coil domain result in its oligomerization at nanomolar concentration. In contrast, the ADF-H domain alone is a monomer, which displays a concentration-dependent self-assembly. In vivo FLIM-FRET imaging shows that the presence of only actin-binding domains is not sufficient for DBNL to localize properly at actin filament inside the cell. In summary, our work provides a detailed insight on structure-function relationship of human drebrin-like protein.

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Drebrin-like protein DBN-1 is a sarcomere component that stabilizes actin filaments during muscle contraction

Cited by 17 publications

References 59 publications

The Inflammatory Transcription Factor C/EBPβ Plays a Critical Role in Cardiac Fibroblast Differentiation and a Rat Model of Cardiac Fibrosis Induced by Autoimmune Myocarditis

The Inflammatory Transcription Factor C/EBPβ Plays a Critical Role in Cardiac Fibroblast Differentiation and a Rat Model of Cardiac Fibrosis Induced by Autoimmune Myocarditis

Drebrin-like protein regulates body bending ofC. elegansvia suppression of NCA cation leak channels

Dimerization of human drebrin-like protein governs its biological activity

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