Regulation of SETD7 Methyltransferase by SENP3 Is Crucial for Sarcomere Organization and Cachexia

Nayak, Arnab; Lopez-Davila, Alfredo J.; Kefalakes, Ekaterini; Holler, Tim; Kraft, Theresia; Amrute-Nayak, Mamta

doi:10.1016/j.celrep.2019.04.107

Cited by 21 publications

(30 citation statements)

References 55 publications

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“…We found that the SUMO isopeptidase, SENP3, is critically required for accurate assembly and arrangement of sarcomeric units within a myofibril. The perturbation in SENP3 levels resulted in dramatic disassembly of sarcomeric structure and loss of contractile ability of myotubes [100]. We demonstrated underlying mechanism, whereby SENP3 modulated SUMO‐dependent epigenetic function of SETD7.…”

Section: Sumo Signaling and Sarcomere Organizationmentioning

confidence: 80%

“…Recently, we uncovered a direct link between SUMO pathway and sarcomere organization. During myogenesis, the overall level of global SUMOylation (SUMO2/3 conjugates) gradually decreased as myoblasts differentiated into mature muscle cells [100]. This indicated crucial involvement of de‐SUMOylation process for this transition phase.…”

Section: Sumo Signaling and Sarcomere Organizationmentioning

confidence: 99%

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SUMO system – a key regulator in sarcomere organization

Nayak

Amrute-Nayak

2020

The FEBS Journal

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Skeletal muscles constitute roughly 40% of human body mass. Muscles are specialized tissues that generate force to drive movements through ATP-driven cyclic interactions between the protein filaments, namely actin and myosin filaments. The filaments are organized in an intricate structure called the 'sarcomere', which is a fundamental contractile unit of striated skeletal and cardiac muscle, hosting a fine assembly of macromolecular protein complexes. The micrometer-sized sarcomere units are arranged in a reiterated array within myofibrils of muscle cells. The precise spatial organization of sarcomere is tightly controlled by several molecular mechanisms, indispensable for its force-generating function. Disorganized sarcomeres, either due to erroneous molecular signaling or due to mutations in the sarcomeric proteins, lead to human diseases such as cardiomyopathies and muscle atrophic conditions prevalent in cachexia. Protein post-translational modifications (PTMs) of the sarcomeric proteins serve a critical role in sarcomere formation (sarcomerogenesis), as well as in the steady-state maintenance of sarcomeres. PTMs such as phosphorylation, acetylation, ubiquitination, and SUMOylation provide cells with a swift and reversible means to adapt to an altered molecular and therefore cellular environment. Over the past years, SUMOylation has emerged as a crucial modification with implications for different aspects of cell function, including organizing higher-order protein assemblies. In this review, we highlight the fundamentals of the small ubiquitin-like modifiers (SUMO) pathway and its link specifically to the mechanisms of sarcomere assembly. Furthermore, we discuss recent studies connecting the SUMO pathway-modulated protein homeostasis with sarcomere organization and muscle-related pathologies.Abbreviations ASH2L, ASH2 Like, Histone Lysine Methyltransferase Complex Subunit; CapZ, F-actin capping protein; Ckm, creatine kinase M-type; cMyBP-C, cardiac myosin binding protein C; Ezh2, enhancer of zeste homolog 2; G9a, euchromatin histone methyltransferase 2; H3K27me3, trimethylation of lysine 27 on histone 3; HDAC, histone deacetylase; hMR-1, human myofibrillogenesis regulator 1; IFN, interferon; Suv39h1, suppressor of variegation 3-9 homolog 1; IjBa, inhibitor of kappa B; Mck, muscle creatine kinase; MEF2d, myocyte enhancer factor-2d; MLCK, myosin light chain kinase; MLL, mixed-lineage leukemia; MLP, muscle LIM protein; MRFs, the myogenic regulatory factors; Myf5, Myc-like basic helix-loop-helix transcription factor; MyHC IIb or Myh2, myosin heavy chain II; MyoD, myoblast determination factor; MYOG, myogenin; NMM II, nonmuscle myosin II; Nse2, non-structural maintenance of chromosome element 2 homolog; Pax7, paired-box 7; PCAF, p300/CBP-associated factor; PcG proteins, polycomb-group proteins; PRC, polycomb repressive complexes; PTMs, post-translational modifications; RLC, regulatory light chains; RNA Pol II, RNA polymerase II; ROS, reactive oxygen species; SAE 1/2, SUMO-activating enzyme 1 or 2; SAE1/2, SUMO E1-a...

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Section: Sumo Signaling and Sarcomere Organizationmentioning

confidence: 80%

Section: Sumo Signaling and Sarcomere Organizationmentioning

confidence: 99%

SUMO system – a key regulator in sarcomere organization

Nayak

Amrute-Nayak

2020

The FEBS Journal

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“…Elute was loaded on SDS‐PAGE and analysed by western blots. Chromatin immunoprecipitation (ChIP) assays were performed according to the published method38. Formaldehyde cross‐linking of myotubes at a final concentration of 1.47% was performed for 10 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Earlier studies established a major role of SENP3 in ribosome maturation 34–36 . In addition, nuclear SENP3 function was also reported to be involved in the regulation of various classes of genes by regulating distinct histone methyltransferase complex such as MLL1/2 and SETD7 complexes 37,38 . One common theme that emerged from all these studies is the importance of catalytic site‐dependent function of SENP3, controlling SUMOylation status of SENP3's interaction partners.…”

Section: Introductionmentioning

confidence: 98%

“…Recently, SENP3 was reported as a key regulator of SETD7‐driven transcriptional programme crucial for correct sarcomere assembly and contractile function of skeletal muscle cells. The SENP3–SETD7 transcriptional regulation was disrupted when muscle atrophy was induced by pro‐inflammatory cytokines 38 . A potential connection of SENP3‐regulated mechanisms with chemotherapy‐induced cachexia however is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Chemotherapy triggers cachexia by deregulating synergetic function of histone‐modifying enzymes

Amrute-Nayak

Pegoli

Holler

et al. 2020

J cachexia sarcopenia muscle

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Background Chemotherapy is the first line of treatment for cancer patients. However, the side effects cause severe muscle atrophy or chemotherapy‐induced cachexia. Previously, the NF‐κB/MuRF1‐dependent pathway was shown to induce chemotherapy‐induced cachexia. We hypothesized that acute collateral toxic effects of chemotherapy on muscles might involve other unknown pathways promoting chemotherapy‐induced muscle atrophy. In this study, we investigated differential effects of chemotherapeutic drugs and probed whether alternative molecular mechanisms lead to cachexia. Methods We employed mouse satellite stem cell‐derived primary muscle cells and mouse C2C12 progenitor cell‐derived differentiated myotubes as model systems to test the effect of drugs. The widely used chemotherapeutic drugs, such as daunorubicin (Daun), etoposide (Etop), and cytarabine (Ara‐C), were tested. Molecular mechanisms by which drug affects the muscle cell organization at epigenetic, transcriptional, and protein levels were measured by employing chromatin immunoprecipitations, endogenous gene expression profiling, co‐immunoprecipitation, complementation assays, and confocal microscopy. Myotube function was examined using the electrical stimulation of myotubes to monitor contractile ability (excitation–contraction coupling) post drug treatment. Results Here, we demonstrate that chemotherapeutic drugs disrupt sarcomere organization and thereby the contractile ability of skeletal muscle cells. The sarcomere disorganization results from severe loss of molecular motor protein MyHC‐II upon drug treatment. We identified that drugs impede chromatin targeting of SETD7 histone methyltransferase and disrupt association and synergetic function of SETD7 with p300 histone acetyltransferase. The compromised transcriptional activity of histone methyltransferase and acetyltransferase causes reduced histone acetylation and low occupancy of active RNA polymerase II on MyHC‐II, promoting drastic down‐regulation of MyHC‐II expression (~3.6‐fold and ~4.5‐fold reduction of MyHC‐IId mRNA levels in Daun and Etop treatment, respectively. P < 0.0001). For MyHC‐IIa, gene expression was down‐regulated by ~2.6‐fold and ~4.5‐fold in Daun and Etop treatment, respectively (P < 0.0001). Very interestingly, the drugs destabilize SUMO deconjugase SENP3. Reduction in SENP3 protein level leads to deregulation of SETD7–p300 function. Importantly, we identified that SUMO deconjugation independent role of SENP3 regulates SETD7–p300 functional axis. Conclusions The results show that the drugs critically alter SENP3‐dependent synergistic action of histone‐modifying enzymes in muscle cells. Collectively, we defined a unique epigenetic mechanism targeted by distinct chemotherapeutic drugs, triggering chemotherapy‐induced cachexia.

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Loss of SENP3 mediated the formation of nasal polyps in nasal mucosal inflammation by increasing alternative activated macrophage

Bao

Liu

Jiang

et al. 2023

Immunity Inflam & Disease

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Background and Aim Small ubiquitin–like modifier (SUMO)‐specific protease (SENP)3 is a protease molecule that responds to reactive oxygen species (ROS) with high sensitivity. However, the role of ROS and SENP3 in the formation of nasal polyps (NPs) remains unclear. This study aimed to explore how SENP3 influenced the outcome of chronic rhinosinusitis (CRS) by altering macrophage function, that is, the formation of NPs. Methods The alternative activation of macrophage (M2) was detected with CD68 + CD206 + in humans and CD206 + in mice. The nasal mucosa of patients with CRS was tested using flow cytometry (CD68, CD80, and CD206) and triple‐color immunofluorescence staining (CD68, CD206, and SENP3). The bone marrow–derived macrophages from SENP3 knockout and control mice were stimulated with interleukin (IL)‐4 and IL‐13 to analyze alternative macrophage polarization in vitro. An animal model of allergic rhinitis was constructed using SENP3 knockout mice. CD206 was detected by immunofluorescence staining. The thickening of eosinophil‐infiltrated mucosa was detected by Luna staining. Results The number of CD68 + CD206 + M2 increased in the nasal mucosa of patients with CRS with NP (CRSwNP) compared with patients with CRS without NP (CRSsNP), but with no significant difference between the groups. SENP3 knockout increased the polarization of F4/80 + CD206 + M2. Meanwhile, the number of CD206 + M2 significantly increased in the allergic rhinitis model constructed using SENP3 knockout mice and controls, with a more obvious proliferation of the nasal mucosa. Conclusion Downregulation of SENP3 promotes the formation of nasal polyps mediated by increasing alternative activated macrophage in nasal mucosal inflammation.

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Regulation of SETD7 Methyltransferase by SENP3 Is Crucial for Sarcomere Organization and Cachexia

Cited by 21 publications

References 55 publications

SUMO system – a key regulator in sarcomere organization

SUMO system – a key regulator in sarcomere organization

Chemotherapy triggers cachexia by deregulating synergetic function of histone‐modifying enzymes

Loss of SENP3 mediated the formation of nasal polyps in nasal mucosal inflammation by increasing alternative activated macrophage

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