Numerous proteins with unique characteristics are degraded by the 26S proteasome following monoubiquitination

The "canonical" proteasomal degradation signal is a substrateanchored polyubiquitin chain. However, a handful of proteins were shown to be targeted following monoubiquitination. In this study, we established-in both human and yeast cells-a systematic approach for the identification of monoubiquitination-dependent proteasomal substrates. The cellular wild-type polymerizable ubiquitin was replaced with ubiquitin that cannot form chains. Using proteomic analysis, we screened for substrates that are nevertheless degraded under these conditions compared with those that are stabilized, and therefore require polyubiquitination for their degradation. For randomly sampled representative substrates, we confirmed that their cellular stability is in agreement with our screening prediction. Importantly, the two groups display unique features: monoubiquitinated substrates are smaller than the polyubiquitinated ones, are enriched in specific pathways, and, in humans, are structurally less disordered. We suggest that monoubiquitination-dependent degradation is more widespread than assumed previously, and plays key roles in various cellular processes

Modulation of chromatin position and gene expression by HDAC4 interaction with nucleoporins

The histone deacetylase HDAC4 associates with the nuclear pore complex component Nup155 to modulate gene expression during cardiomyocyte hypertrophy

Towards standardization of echocardiography for the evaluation of left ventricular function in adult rodents : a position paper of the ESC Working Group on Myocardial Function

This work was supported by AIRC IG grant 2016 19032 to S.Z.; FEDER through Compete 2020 –Programa Operacional Competitividade E Internacionalização(POCI), the project DOCNET (norte-01-0145-feder-000003), supported by Norte Portugal regional operational programme (norte 2020), under the Portugal 2020 partnership agreement, through the European Regional Development Fund (ERDF), the project NETDIAMOND (POCI-01-0145-FEDER-016385), supported by European Structural And Investment Funds, Lisbon’s regional operational program 2020 to I.P.F.; grants from FSR-FNRS, FRC (Cliniques Universitaires Saint-Luc) and from Action de Recherche Concertée (UCLouvain) to C.B., E.P.D. and L.B; the ERA-Net-CVD project MacroERA,01KL1706, FP7-Homage N° 305507, and IMI2-CARDIATEAM (N° 821508)to S.H.,the DZHK (German Centre for Cardiovascular Research) and the German Ministry of Research and Education (BMBF)to F.W., T.E. and L.C., the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, grant 2017-21, CVON Arena-PRIME, 2017-18, Flemish Research FoundationFWO G091018N and FWO G0B5930N to S.H.; Federico II University/Ricerca di Ateneo grant to C.G..T.; the European Research Area Networks on Cardiovascular Diseases (ERA-CVD) [LYMIT-DIS 2016, MacroERA], Fonds Wetenschappelijk Onderzoek [1160718N] to I.C; the Deutsche Forschungsgemeinschaft (DFG TH903/20-1, KFO311), the Transregio-SFB INST 95/15641 and the EU Horizon 2020 project Cardioregenix (GA 825670)to T.TPeer reviewedPostprin

Novel Strategies for the Treatment of Heart Failure

Heart failure is a leading cause of morbidity and mortality with a prevalence that is rising throughout the world. Currently the pharmaceutical therapy of heart failure is mainly based on inhibition of the neurohumoral pathways that are activated secondary to the deterioration of cardiac function, and diuretics to alleviate the salt and water overload. With our increasing understanding of the pathophysiology of heart failure, it is now clear that the macroscopic and functional changes in the failing heart result from remodeling at the cellular, interstitial, and molecular levels. Therefore, emerging therapies propose to intervene directly in the remodeling process at the cellular and the molecular levels. Here, several experimental strategies that aim to correct the abnormalities in receptor and post-receptor-function, calcium handling, excitation and contraction coupling, signaling, and changes in the extra-cellular matrix in the failing heart will be discussed. These novel approaches, aiming to reverse the remodeling process at multiple levels, may appear on the clinical arena in the coming years

Correction: Adult Cardiac Expression of the Activating Transcription Factor 3, ATF3, Promotes Ventricular Hypertrophy.

[This corrects the article DOI: 10.1371/journal.pone.0068396.]

Adult Cardiac Expression of the Activating Transcription Factor 3, ATF3, Promotes Ventricular Hypertrophy

<div><p>Cardiac hypertrophy is an adaptive response to various mechanophysical and pathophysiological stresses. However, when chronic stress is sustained, the beneficial response turns into a maladaptive process that eventually leads to heart failure. Although major advances in the treatment of patients have reduced mortality, there is a dire need for novel treatments for cardiac hypertrophy. Accordingly, considerable efforts are being directed towards developing mice models and understanding the processes that lead to cardiac hypertrophy. A case in point is ATF3, an immediate early transcription factor whose expression is induced in various cardiac stress models but has been reported to have conflicting functional significance in hypertrophy. To address this issue, we generated a transgenic mouse line with tetracycline-regulated ATF3 cardiac expression. These mice allowed us to study the consequence of ATF3 expression in the embryo or during the adult period, thus distinguishing the effect of ATF3 on development versus pathogenesis of cardiac dysfunction. Importantly, ATF3 expression in adult mice resulted in rapid ventricles hypertrophy, heart dysfunction, and fibrosis. When combined with a phenylephrine-infusion pressure overload model, the ATF3 expressing mice displayed a severe outcome and heart dysfunction. In a complementary approach, ATF3 KO mice displayed a lower level of heart hypertrophy in the same pressure overload model. In summary, ectopic expression of ATF3 is sufficient to promote cardiac hypertrophy and exacerbates the deleterious effect of chronic pressure overload; conversely, ATF3 deletion protects the heart. Therefore, ATF3 may serve as an important drug target to reduce the detrimental consequences of heart hypertrophy.</p> </div

Adult-ATF3 expression promotes hypertrophy.

<p>A. Mice were mated in the presence of doxycycline (adult ATF3 expressing). Weaned newborn mice were either maintained with doxycycline containing water (0 weeks without doxycycline) or provided with regular water. Mice were sacrificed at the indicated number of weeks following doxycycline removal. Mice ventricles were weighed (Vw) to mouse body weight (Bw). The results represent the ratio of Vw/Bw (mg/gr) of ATF3 transgenic mice (gray) and wild-type (black) mice at the indicated time (weeks) following doxycycline removal. The results represent the mean and SEM of the indicated number of animals (n). <b>B</b>. Atria and ventricles weight relative to body weight at 6 weeks of age (mg/gr). <b>C</b>–<b>F</b>. Adult-ATF3 expressing mice show higher expression of hypertrophic markers. RT-qPCR analysis for cDNA derived from RNA extracted from ventricles of ATF3-transgenic and wild-type mice with the corresponding specific primers to the following genes: <b>C</b>. Atrial natriuretic peptide (ANP) D. Brain natriuretic peptide (BNP) <b>E</b>. β Myosin heavy chain (βMHC) F. Skeletal actin (Acta1). The results represent the mean expression relative to GAPDH of the indicated number of animals (n). <b>G</b>. Ventricles sections were stained with TRITC-labeled wheat germ aglutinin and the cell size was analyzed using the Image Pro Plus software. <b>H</b>. Quantification of cell size in G. The results represent the mean and SEM from five different sections derived from wild type (n=2) and adult ATF3 expressing (n=3) animals at the indicated time following doxycycline removal. Asterisks (*/**) represent P value <0.05 or <0.01 respectively of a one-tailed t-test compared with wild-type mice.</p