Heart muscle maintains blood circulation, while skeletal muscle powers skeletal movement. Despite having similar myofibrilar sarcomeric structures, these striated muscles differentially express specific sarcomere components to meet their distinct contractile requirements. The mechanism responsible is still unclear. We show here that preservation of the identity of the two striated muscle types depends on epigenetic repression of the alternate lineage gene program by the chromatin remodeling complex Chd4/NuRD. Loss of Chd4 in the heart triggers aberrant expression of the skeletal muscle program, causing severe cardiomyopathy and sudden death. Conversely, genetic depletion of Chd4 in skeletal muscle causes inappropriate expression of cardiac genes and myopathy. In both striated tissues, mitochondrial function was also dependent on the Chd4/NuRD complex. We conclude that an epigenetic mechanism controls cardiac and skeletal muscle structural and metabolic identities and that loss of this regulation leads to hybrid striated muscle tissues incompatible with life.

The inhibitor of the nuclear factor-κB (IκB) kinase (IKK) complex is a key regulator of the canonical NF-κB signalling cascade and is crucial for fundamental cellular functions, including stress and immune responses. The majority of IKK complex functions are attributed to NF-κB activation; however, there is increasing evidence for NF-κB pathway-independent signalling. Here we combine quantitative mass spectrometry with random forest bioinformatics to dissect the TNF-α-IKKβ-induced phosphoproteome in MCF-7 breast cancer cells. In total, we identify over 20,000 phosphorylation sites, of which ∼1% are regulated up on TNF-α stimulation. We identify various potential novel IKKβ substrates including kinases and regulators of cellular trafficking. Moreover, we show that one of the candidates, AEG-1/MTDH/LYRIC, is directly phosphorylated by IKKβ on serine 298. We provide evidence that IKKβ-mediated AEG-1 phosphorylation is essential for IκBα degradation as well as NF-κB-dependent gene expression and cell proliferation, which correlate with cancer patient survival in vivo.

The pleiotropic interleukin-6 (IL-6)-type cytokine oncostatin M (OSM) signals in multiple cell types, affecting processes such as cell differentiation, hematopoiesis, and inflammation. In humans, OSM exerts its effects through activation of either of two different heterodimeric receptor complexes, formed by glycoprotein 130 (gp130) and either OSM receptor (OSMR) or leukemia inhibitory factor receptor (LIFR). In contrast, the mouse OSM orthologue acts mainly through dimers containing OSMR and gp130 and shows limited activity through mouse LIFR. Despite their structural similarity, neither human nor mouse OSM signal through the other species' OSMR. The molecular basis for such species-specific signaling, however, remains poorly understood. To identify key molecular features of OSM that determine receptor activation in humans and mice, we generated chimeric mouse-human cytokines. Replacing regions within binding site III of murine OSM with the human equivalents showed that the cytokine's AB loop was critical for receptor selection. Substitutions of individual amino acids within this region demonstrated that residues Asn-37, Thr-40, and Asp-42 of the murine cytokine were responsible for limited LIFR activation and absence of human OSMR/LIFR signaling. In human OSM, Lys-44 appeared to be the main residue preventing mouse OSMR activation. Our data reveal that individual amino acids within the AB loop of OSM determine species-specific activities. These mutations might reflect a key step in the evolutionary process of this cytokine, in which receptor promiscuity gives way to ligand-receptor specialization. . 3 The abbreviations used are: IL-6, interleukin-6; OSM, oncostatin M; hOSM and mOSM, human and mouse OSM, respectively; LIF, leukemia inhibitory factor; hLIF and mLIF, human and mouse LIF, respectively; gp130, glycoprotein 130; OSMR, oncostatin M receptor; hOSMR and mOSMR, human and mouse OSMR, respectively; LIFR, leukemia inhibitory factor receptor; hLIFR and mLIFR, human and mouse LIFR, respectively; MAPK, mitogenactivated protein kinase; PI3K/Akt, phosphoinositide 3-kinase/protein kinase B; STAT, signal transducer and activator of transcription; P-STAT, phosphorylated STAT; TIMP1, tissue inhibitor of metalloproteinase 1; BisTris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol; JNK, c-Jun N-terminal kinase.Figure 14. Proposed model of OSM evolution. A, phylogeny inference analysis of OSM orthologues. B, proposed two-step model of OSM evolution, in which spatial rearrangements in the AB loop and D-helix initially enabled OSMR activation and acquisition of new biological function. Subsequently, point mutations in the OSM AB loop resulted in receptor and functional specialization in mice. *, This research was originally published in Journal of Biological Chemistry. Adrian-Segarra, J. M., Schindler, N., Gajawada, P., Lörchner, H., Braun, T., and Pö ling, J. The AB loop and D-helix in binding site III of human Oncostatin M (OSM) are required for OSM receptor activation. J. Biol. Chem. 2018; 293:7017-7029...

Highlights d Necroptotic cell death of MuSCs is essential for efficient muscle regeneration d Inhibition of necroptosis exacerbates adverse crosstalk among mdx muscle stem cells d The CHD4/NuRD complex directly represses Ripk3dependent necroptosis d Attenuated recruitment of CHD4 to Ripk3 locus lowers necroptosis threshold in dystrophy

No abstract