SUMO-Specific Protease 2 (SENP2) Is an Important Regulator of Fatty Acid Metabolism in Skeletal Muscle

Yd, Koo; Jw, Choi; Kim, Mi‐Hyun; Chae, Sehyun; Ahn, Byung Yong; Oh, Byung‐Chul; Hwang, Dong Soo; Jh, Seol; Yb, Kim; Yj, Park; Ss, Chung; Ks, Park

doi:10.2337/db15-0115

Cited by 51 publications

(56 citation statements)

References 47 publications

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“…Based on this example, a more widespread role of SUMOs can be envisaged for muscle cell function. A recent finding of SENP2 in fatty acid metabolism in skeletal muscle cells is the testimony of this speculation [102]. Our observations that the muscle atrophic condition can be partially restored to a normal level by modulating the SUMOylation process provide the potential tool to intervene in the pathologies associated with the compromised muscle function due to myofibrillar disarray.…”

Section: Discussionmentioning

confidence: 60%

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: Discussionmentioning

confidence: 60%

SUMO system – a key regulator in sarcomere organization

Nayak

Amrute-Nayak

2020

The FEBS Journal

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“…SENP2 regulates adipogenesis via de-SUMOylation of C/EBPβ, which in turn promotes C/EBPα and PPARγ28, and controls glucose metabolism via p-AKT9. Overexpression of SENP2 promotes fatty acid metabolism in skeletal muscle via fatty acid oxidation, ultimately alleviating obesity-linked metabolic disorders10. On the other hand, SENP2 silence attenuates adipogenesis in preadipocytes28.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that overexpressed SENP1 promotes mitochondrial biogenesis and function in myotubes8. SENP2 inhibits glycolysis, reprograms glucose metabolic strategy in cancer cells9 and regulates fatty acid metabolism in skeletal muscle10, suggesting an important role of SENP2 in metabolic disorders. SENP5 is reported to maintain mitochondrial morphology and metabolism11.…”

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confidence: 99%

SUMO-specific protease 3 is a key regulator for hepatic lipid metabolism in non-alcoholic fatty liver disease

Liu

et al. 2016

Sci Rep

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Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes. The role of SENP3 in lipid metabolism, particularly NAFLD, is unclear. Our results showed that hepatic SENP3 was up-regulated in NAFLD patients and an animal model in vivo and after loading hepatocytes with free fatty acids (FFA) in vitro. Intracellular lipid accumulation was determined in SENP3 silenced or overexpressed hepatocytes with/without FFA in vitro. Confirming a role for SENP3, gene silencing was associated in vitro with amelioration of lipid accumulation and overexpression with enhancement of lipid accumulation. SENP3 related genes in NAFLD were determined in vitro using RNA-Seq. Eleven unique genes closely associated with lipid metabolism were generated using bioinformatics. Three selected genes (apoe, a2m and tnfrsf11b) were verified in vitro, showing apoe, a2m and tnfrsf11b were regulated by SENP3 with FFA stimulation. Intrahepatic and circulating APOE, A2M and TNFRSF11B were elevated in NAFLD compared with controls. These data demonstrate the important role of SENP3 in lipid metabolism during the development of NAFLD via downstream genes, which may be useful information in the development of NAFLD. The precise role of SENP3 in NAFLD will be investigated using liver-specific conditional knockout mice in future studies.

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“…Ad-h SENP2 prepared as previously described 23 was generously provided by Professor Kyong Soo Park (Seoul National University). INS1 cells at 70∼80% confluence were transfected with adenovirus containing a construct expressing green fluorescent protein (Ad-GFP) and Ad-h SENP2 at a multiplicity of infection of 45.…”

Section: Methodsmentioning

confidence: 99%

Senp2 expression was induced by chronic glucose stimulation in INS1 cells, and it was required for the associated induction of Ccnd1 and Mafa

Jung

Kang²,

Park

et al. 2016

Islets

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Post-translational modification by bonding of small ubiquitin-like modifier (SUMO) peptides influences various cellular functions, and is regulated by SUMO-specific proteases (SENPs). Several proteins have been suggested to have diverse impact on insulin synthesis and secretion through SUMO modification in β cells. However, the role of SUMO modification in β cell mass has not been established. Here, we examined the changes in expression of Senp in INS1 cells and pancreatic islets under diabetes-relevant stress conditions and associated changes in β cell mass. Treatment with 25 mM glucose for 72 h induced Senp2 mRNA expression but not that of Senp1 in INS1 cells. Immunohistochemical staining with anti-SENP2 antibody on human pancreas sections revealed that SENP2 was localized in the nucleus. Moreover, in a patient with type 2 diabetes, SENP2 levels were enhanced, especially in the cytoplasm. Senp2 cytoplasmic levels were also increased in islet cells in obese diabetic mice. Cell number peaked earlier in INS1 cells cultured in high-glucose conditions compared to those cultured in control media. This finding was associated with increased Ccnd1 mRNA expression in high-glucose conditions, and siRNA-mediated Senp2 suppression abrogated it. Mafa expression, unlike Pdx1, was also dependent on Senp2 expression during high-glucose conditions. In conclusion, Senp2 may play a role in β cell mass in response to chronic high-glucose through Cyclin D1 and Mafa.

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SUMO-Specific Protease 2 (SENP2) Is an Important Regulator of Fatty Acid Metabolism in Skeletal Muscle

Cited by 51 publications

References 47 publications

SUMO system – a key regulator in sarcomere organization

SUMO system – a key regulator in sarcomere organization

SUMO-specific protease 3 is a key regulator for hepatic lipid metabolism in non-alcoholic fatty liver disease

Senp2 expression was induced by chronic glucose stimulation in INS1 cells, and it was required for the associated induction of Ccnd1 and Mafa

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