OTUB1 alleviates NASH through inhibition of the TRAF6-ASK1 signaling pathways.

BACKGROUND AND AIMS: NAFLD is considered as the hepatic manifestation of the metabolic syndrome, which includes insulin resistance, obesity and hyperlipidemia. NASH is a progressive stage of NAFLD with severe hepatic steatosis, hepatocyte death, inflammation, and fibrosis. Currently, no pharmacological interventions specifically tailored for NASH are approved. Ovarian tumor domain, ubiquitin aldehyde binding 1 (OTUB1), the founding member of deubiquitinases, regulates many metabolism-associated signaling pathways. However, the role of OTUB1 in NASH is unclarified. METHODS AND RESULTS: We demonstrated that mice with Otub1 deficiency exhibited aggravated high-fat diet-induced and high-fat high-cholesterol (HFHC) diet-induced hyperinsulinemia and liver steatosis. Notably, hepatocyte-specific overexpression of Otub1 markedly alleviated HFHC diet-induced hepatic steatosis, inflammatory responses, and liver fibrosis. Mechanistically, we identified apoptosis signal-regulating kinase 1 (ASK1) as a key candidate target of OTUB1 through RNA-sequencing analysis and immunoblot analysis. Through immunoprecipitation-mass spectrometry analysis, we further found that OTUB1 directly bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) and suppressed its lysine 63-linked polyubiquitination, thus inhibiting the activation of ASK1 and its downstream pathway. CONCLUSIONS: OTUB1 is a key suppressor of NASH that inhibits polyubiquitinations of TRAF6 and attenuated TRAF6-mediated ASK1 activation. Targeting the OTUB1-TRAF6-ASK1 axis may be a promising therapeutic strategy for NASH.

Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal-Regulating Kinase 1 Pathways.

Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Due to the growing economic burden of NAFLD on public health, it has become an emergent target for clinical intervention. DUSP12 is a member of the dual specificity phosphatase (DUSP) family, which plays important roles in brown adipocyte differentiation, microbial infection, and cardiac hypertrophy. However, the role of DUSP12 in NAFLD has yet to be clarified. Here, we reveal that DUSP12 protects against hepatic steatosis and inflammation in L02 cells after palmitic acid/oleic acid treatment. We demonstrate that hepatocyte specific DUSP12-deficient mice exhibit high-fat diet (HFD)-induced and high-fat high-cholesterol diet-induced hyperinsulinemia and liver steatosis and decreased insulin sensitivity. Consistently, DUSP12 overexpression in hepatocyte could reduce HFD-induced hepatic steatosis, insulin resistance, and inflammation. At the molecular level, steatosis in the absence of DUSP12 was characterized by elevated apoptosis signal-regulating kinase 1 (ASK1), which mediates the mitogen-activated protein kinase (MAPK) pathway and hepatic metabolism. DUSP12 physically binds to ASK1, promotes its dephosphorylation, and inhibits its action on ASK1-related proteins, JUN N-terminal kinase, and p38 MAPK in order to inhibit lipogenesis under high-fat conditions. Conclusion: DUSP12 acts as a positive regulator in hepatic steatosis and offers potential therapeutic opportunities for NAFLD.

Description of three new species of Ooencyrtus (Hymenoptera: Encyrtidae) from China.

Hymenoptera parasitoids of Megaloptera, particularly the family Corydalidae, are rarely found. Ooencyrtus Ashmead is a genus that attacks eggs of many orders of Insecta, including Megaloptera. Here, three species, O. longicauda sp. n., O. noyesi sp. n. and O. protohermeasis sp. n. are described. Two of them, O. longicauda and O. protohermesis were reared from eggs of corydalids (Megaloptera: Corydalidae). The three new species and O. yoshidai Noyes & Hirose are included in the newly established protohermesis species-group of Ooencyrtus because of shared similar morphological characters and what is apparently a shared host family (unknown for O. noyesi).

Melanoma differentiation-associated protein 5 prevents cardiac hypertrophy via apoptosis signal-regulating kinase 1-c-Jun N-terminal kinase/p38 signaling.

Pathological cardiac hypertrophy (CH) is driven by maladaptive changes in myocardial cells in response to pressure overload or other stimuli. CH has been identified as a significant risk factor for the development of various cardiovascular diseases, ultimately resulting in heart failure. Melanoma differentiation-associated protein 5 (MDA5), encoded by interferon-induced with helicase C domain 1 (IFIH1), is a cytoplasmic sensor that primarily functions as a detector of double-stranded ribonucleic acid (dsRNA) viruses in innate immune responses; however, its role in CH pathogenesis remains unclear. Thus, the aim of this study was to examine the relationship between MDA5 and CH using cellular and animal models generated by stimulating neonatal rat cardiomyocytes with phenylephrine and by performing transverse aortic constriction on mice, respectively. MDA5 expression was upregulated in all models. MDA5 deficiency exacerbated myocardial pachynsis, fibrosis, and inflammation in vivo, whereas its overexpression hindered CH development in vitro. In terms of the underlying molecular mechanism, MDA5 inhibited CH development by promoting apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, thereby suppressing c-Jun N-terminal kinase/p38 signaling pathway activation. Rescue experiments using an ASK1 activation inhibitor confirmed that ASK1 phosphorylation was essential for MDA5-mediated cell death. Thus, MDA5 protects against CH and is a potential therapeutic target.

A chromosome-level genome assembly of the forestry pest Coronaproctus castanopsis.

As an important forestry pest, Coronaproctus castanopsis (Monophlebidae) has caused serious damage to the globally valuable Gutianshan ecosystem, China. In this study, we assembled the first chromosome-level genome of the female specimen of C. castanopsis by merging BGI reads, HiFi long reads and Hi-C data. The assembled genome size is 700.81 Mb, with a scaffold N50 size of 273.84 Mb and a contig N50 size of 12.37 Mb. Hi-C scaffolding assigned 98.32% (689.03 Mb) of C. Castanopsis genome to three chromosomes. The BUSCO analysis (n = 1,367) showed a completeness of 91.2%, comprising 89.2% of single-copy BUSCOs and 2.0% of multicopy BUSCOs. The mapping ratio of BGI, second-generation RNA, third-generation RNA and HiFi reads are 97.84%, 96.15%, 97.96%, and 99.33%, respectively. We also identified 64.97% (455.3 Mb) repetitive elements, 1,373 non-coding RNAs and 10,542 protein-coding genes. This study assembled a high-quality genome of C. castanopsis, which accumulated valuable molecular data for scale insects.

Cophylogenetic relationships between Anicetus parasitoids (Hymenoptera: Encyrtidae) and their scale insect hosts (Hemiptera: Coccidae).

BACKGROUND: Numerous studies have investigated cospeciation between parasites and their hosts, but there have been few studies concerning parasitoids and insect hosts. The high diversity and host specialization observed in Anicetus species suggest that speciation and adaptive radiation might take place with species diversification in scale insect hosts. Here we examined the evolutionary history of the association between Anicetus species and their scale insect hosts via distance-based and tree-based methods. RESULTS: A total of 94 Anicetus individuals (nine parasitoid species) and 113 scale insect individuals (seven host species) from 14 provinces in China were collected in the present study. DNA sequence data from a mitochondrial gene (COI) and a nuclear ribosomal gene (28S D2 region) were used to reconstruct the phylogenies of Anicetus species and their hosts. The distance-based analysis showed a significant fit between Anicetus species and their hosts, but tree-based analyses suggested that this significant signal could be observed only when the cost of host-switching was high, indicating the presence of parasite sorting on related host species. CONCLUSIONS: This study, based on extensive rearing of parasitoids and species identification, provides strong evidence for a prevalence of sorting events and high host specificity in the genus Anicetus, offering insights into the diversification process of Anicetus species parasitizing scale insects.

Salimesophilobacter vulgaris gen. nov., sp. nov., an anaerobic bacterium isolated from paper-mill wastewater.

A novel anaerobic, heterotrophic bacterium, designated strain Zn2(T), was isolated from the wastewater of a paper mill in Zhejiang, China. Cells were gram-type-positive rods, 0.5-0.8 µm wide and 2-4 µm long, and were motile by a lateral flagellum. The ranges of temperature and pH for growth were 10-50 °C and pH 6.0-9.5. Optimal growth occurred at 35 °C and pH 7.3-7.5. The strain did not require NaCl for growth, but its inclusion in the medium improved growth (optimum concentration 6 %). Substrates utilized as sole carbon sources were peptone, tryptone, Casamino acids, D-xylose, salicin, glycerol, formate, acetate and propionate. The main products of carbohydrate fermentation were acetate, formate, propionate and lactate. Elemental sulfur, thiosulfate and Fe(III) were used as electron acceptors, but sulfate, sulfite, nitrate, nitrite and Mn(IV) were not. Growth was inhibited by the addition of 10 µg ampicillin, penicillin, tetracycline or chloramphenicol ml(-1). iso-C15 : 0, C14 : 0, C16 : 0, C16 : 1 cis9 and C18 : 1 cis9 were the major fatty acids. Strain Zn2(T) did not contain any detectable menaquinones or ubiquinones. The main polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, two unknown phospholipids and four unknown glycolipids. The genomic DNA G+C content was 37 mol%, as determined by HPLC. 16S rRNA gene sequence analysis revealed that strain Zn2(T) was a member of family Clostridiaceae, and was most closely related to the type strains of Geosporobacter subterraneus, Thermotalea metallivorans and Caminicella sporogenes, showing 91.2, 90.3 and 91.1 % sequence similarity, respectively. On the basis of its phenotypic and genotypic properties, strain Zn2(T) is suggested to represent a novel species of a new genus, for which the name Salimesophilobacter vulgaris gen. nov., sp. nov. is proposed. The type strain of Salimesophilobacter vulgaris is Zn2(T) ( = DSM 24770(T)  = JCM 17796(T)).

Oceanirhabdus sediminicola gen. nov., sp. nov., an anaerobic bacterium isolated from sea sediment.

A novel anaerobic bacterium, designated NH-JN4(T) was isolated from a sediment sample collected in the South China Sea. Cells were Gram-stain-positive, spore-forming, peritrichous and rod-shaped (0.5-1.2×2.2-7 µm). The temperature and pH ranges for growth were 22-42 °C and pH 6.0-8.5. Optimal growth occurred at 34-38 °C and pH 6.5-7.0. The NaCl concentration range for growth was 0.5-6 % (w/v) with an optimum of 2.5 %. Catalase and oxidase were not produced. Substrates which could be utilized were peptone, tryptone, yeast extract, beef extract and glycine. Main fermentation products from PYG medium were formate, acetate, butyrate and ethanol. Strain NH-JN4(T) could utilize sodium sulfite as an electron acceptor. No respiratory quinone was detected. The predominant fatty acids were anteiso-C15 : 0, C16 : 0, iso-C15 : 0, anteiso-C17 : 0 and C16 : 0 DMA. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and glycolipids. The DNA G+C content was 35.8 mol%. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain NH-JN4(T) was a member of family Clostridiaceae, and was most closely related to Clostridium limosum ATCC 25620(T), Clostridium proteolyticum DSM 3090(T), Clostridium histolyticum ATCC 19401(T) and Clostridium tepidiprofundi SG 508(T), showing 94.0, 93.0, 92.9 and 92.3 % sequence similarity, respectively. On the basis of phenotypic, genotypic and chemotaxonomic properties, strain NH-JN4(T) represents a novel species of a new genus in the family Clostridiaceae, for which the name Oceanirhabdus sediminicola gen. nov., sp. nov. is proposed. The type strain of the type species is NH-JN4(T) ( = JCM 18501(T) = CCTCC AB 2013103(T) = KCTC 15322(T)).

Two new species of Coccophagus Westwood (Hymenoptera: Aphelinidae) from China.

The malthusi group of Coccophagus Westwood (Hymenoptera: Aphelinidae) is characterized by a densely setose mesoscutellum with the posterior apical pair of setae distinctly longer than others. In the present paper, two new species of the malthusi group are described from China: Coccophagus infuscatus sp. nov. and Coccophagus bandus sp. nov., both reared from species of Coccidae (Hemiptera: Sternorrhyncha). The type specimens are housed in Institute of Zoology, Chinese Academy of Sciences (IZCAS), Beijing, China.

Brassicibacter mesophilus gen. nov., sp. nov., a strictly anaerobic bacterium isolated from food industry wastewater.

A novel mesophilic, strictly anaerobic bacterium, strain BM(T), was isolated from food industry wastewater. The cells were motile, non-spore-forming rods and stained Gram-negative. Growth of strain BM(T) was observed at 16-44 °C (optimum 37 °C) and pH 6.0-9.0 (optimum pH 7.5). The NaCl concentration range for growth was 0-8% (optimum 1.5%, w/v). Strain BM(T) was chemo-organotrophic, using a few sugars and amino acids as sole carbon and energy sources. The fermentation products from peptone-yeast extract broth were propionate, formate, acetate, ethanol and isovalerate. Indole, NH(3) and H(2)S were produced from peptone. No respiratory quinones could be detected. The major fatty acids were iso-C(15:0) (39.3%), iso-C(15:0) dimethyl acetal (10.1%), anteiso-C(15:0) (7.6%), C(14:0) (6.1%) and C(16:0) (5.6%). The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol and a number of unidentified aminoglycolipids, glycolipids and phospholipids. The DNA G+C content was 28.2 mol%. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain BM(T) was related to various genera of the family Clostridiaceae, and its closest relatives were Sporosalibacterium faouarense SOL3f37(T) (94.3% 16S rRNA gene sequence similarity), Proteiniborus ethanoligenes GW(T) (92.1%) and Clostridiisalibacter paucivorans 37HS60(T) (92.0%). In recognition of its distinct phenotypic and genotypic characteristics, isolate BM(T) is proposed to represent a novel species of a new genus, Brassicibacter mesophilus gen. nov., sp. nov. The type strain of Brassicibacter mesophilus is BM(T) ( = JCM 16868(T)  = DSM 24659(T)).

Dual-specificity phosphatase 12 attenuates oxidative stress injury and apoptosis in diabetic cardiomyopathy via the ASK1-JNK/p38 signaling pathway.

Diabetic cardiomyopathy (DCM) is ventricular dysfunction that occurs in patients with diabetes mellitus (DM), independent of recognized risk factors, such as coronary artery disease, hypertension, and valvular heart disease. Dual-specificity phosphatase 12 (DUSP12) is a dual-specificity phosphatase expressed in all tissues. Genome-wide linkage studies have found an association between DUSP12 and type 2 diabetes (T2D). However, the role of DUSP12 in DCM remains largely unknown. Ubiquitously expressed DUSP12 is involved in nonalcoholic fatty liver disease, bacterial infection, and myocardial hypertrophy and plays a critical role in tumorigenesis. Herein, we observed an increased expression of DUSP12 in a hyperglycemia cell model and a high-fat diet (HFD) mouse model. Heart-specific DUSP12-deficient mice showed severe cardiac dysfunction and remodeling induced by an HFD. DUSP12 deficiency exacerbated oxidative stress injury and apoptosis, whereas DUSP12 overexpression had the opposite effect. At the molecular level, DUSP12 physically bound to apoptotic signal-regulated kinase 1 (ASK1), promoted its dephosphorylation, and inhibited its action on c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Rescue experiments have shown that oxidative stress injury and apoptosis, exacerbated by DUSP12 deficiency, are alleviated by ASK1 inhibition. Therefore, we consider DUSP12 an important signaling pathway in DCM.

E3 ubiquitin ligase RNF5 attenuates pathological cardiac hypertrophy through STING.

Ring-finger protein 5 (RNF5) is an E3 ubiquitin ligase which is expressed in a variety of human tissues. RNF5 is involved in the regulation of endoplasmic reticulum stress, inflammation, and innate immunity and plays an important role in the occurrence and development of various tumors. However, the role of RNF5 in cardiac hypertrophy has not been reported. In this study, we found the expression of RNF5 was increased in the hearts of mice with pathological cardiac hypertrophy. The loss-of-function research demonstrated that RNF5 deficiency exacerbated cardiac hypertrophy, whereas gain-of-function studies revealed that overexpression of RNF5 had opposite effects. The stimulator of interferon genes (STING) is a signaling molecule that can activate type I interferon immunity, which can meditate inflammation and immune response in many diseases. The protein-protein interaction experiments confirmed that STING interacted with RNF5. Further studies showed that RNF5 inhibited cardiac hypertrophy by promoting STING degradation through K48-linked polyubiquitination. Therefore, we defined RNF5 as importantly regulated signaling for cardiac hypertrophy.

Myotubularin-Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo-Like Kinase1.

Background Restenosis is one of the main bottlenecks in restricting the further development of cardiovascular interventional therapy. New signaling molecules involved in the progress have continuously been discovered; however, the specific molecular mechanisms remain unclear. MTMR14 (myotubularin-related protein 14) is a novel phosphoinositide phosphatase that has a variety of biological functions and is involved in diverse biological processes. However, the role of MTMR14 in vascular biology remains unclear. Herein, we addressed the role of MTMR14 in neointima formation and vascular smooth muscle cell (VSMC) proliferation after vessel injury. Methods and Results Vessel injury models were established using SMC-specific conditional MTMR14-knockout and -transgenic mice. Neointima formation was assessed by histopathological methods, and VSMC proliferation and migration were assessed using fluorescence ubiquitination-based cell cycle indicator, transwell, and scratch wound assay. Neointima formation and the expression of MTMR14 was increased after injury. MTMR14 deficiency accelerated neointima formation and promoted VSMC proliferation after injury, whereas MTMR14 overexpression remarkably attenuated this process. Mechanistically, we demonstrated that MTMR14 suppressed the activation of PLK1 (polo-like kinase 1) by interacting with it, which further leads to the inhibition of the activation of MEK/ERK/AKT (mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase/protein kinase B), thereby inhibiting the proliferation of VSMC from the medial to the intima and thus preventing neointima formation. Conclusions MTMR14 prevents neointima formation and VSMC proliferation by inhibiting PLK1. Our findings reveal that MTMR14 serves as an inhibitor of VSMC proliferation and establish a link between MTMR14 and PLK1 in regulating VSMC proliferation. MTMR14 may become a novel potential therapeutic target in the treatment of restenosis.

Two new species of Microterys Thomson, 1876 (Hymenoptera: Encyrtidae) from Tibet, China.

Two new species of Microterys (Hymenoptera: Encyrtidae), Microterys motuoensis Li Zhang sp. nov. and Microterys tibetensis Li Zhang sp. nov., are described from Tibet, China. Microterys motuoensis was reared from Kermes sp. (Hemiptera: Kermesidae) on Castanea sp. (Fagales: Fagaceae), and Microterys tibetensis from Saissetia sp. (Hemiptera: Coccidae) on Tetracera sarmentosa Vahl. (Dilleniales: Dilleniaceae).

Investigating the Parasitoid Community Associated with the Invasive Mealybug Phenacoccus solenopsis in Southern China.

The cotton mealybug Phenacoccus solenopsis Tinsley (Hemiptera: Pseudococcidae), is an emerging invasive insect pest in China. Hymenopteran parasitoids are the key organisms for suppressing populations of P. solenopsis in the field, and therefore could be used as biological agents. Accurate identification of the associated parasitoids is the critical step to assess their potential role in biological control. In this study, we facilitated the identification of the parasitoid composition of P. solenopsis using an integrated approach of species delimitation, combining morphology with molecular data. Eighteen Hymenoptera parasitoid species belonging to 11 genera of four families are recognized based on morphological examination and molecular species delimitation of the mitochondrial cytochrome c oxidase 1 (COI) gene and the 28S rDNA using the automatic barcode gap discovery (ABGD) and the Bayesian Poisson tree processes model (bPTP). Among these species, eight species are primary parasitoids with Aenasius arizonensis (Girault) (Hymenoptera: Encyrtidae) being the dominant taxon, while the other 10 species are probably hyperparasitoids, with a prevalence of Cheiloneurus nankingensis Li & Xu (Hymenoptera: Encyrtidae). These results indicate that parasitoid wasps associated with P. solenopsis from China are diverse and the integrated taxonomic approach applied in this study could enhance the accurate identification of these parasitoids that should be assessed in future biological control programs.

The complete mitochondrial genome of Metaphycus eriococci (Timberlake) (Hymenoptera: Encyrtidae).

The complete mitochondrial genome of the Metaphycus eriococci (Timberlake, 1916) (Hymenoptera: Encyrtidae) was obtained via next-generation sequencing. This mitochondrial genome is 15,749 bp in length with 37 classical eukaryotic mitochondrial genes and an A + T-rich region. All the 13 PCGs begin with typical ATN codons. Among them, 12 PCG genes terminate with TAA, only one with TAG. All of the 22 tRNA genes, ranging from 58 to 72 bp with typical cloverleaf structure except for trnS1 and trnE, whose dihydrouridine arm forms a simple loop. A dramatic gene rearrangement with a large inversion of six protein-coding genes (nad3-cox3-atp6-atp8-cox2-cox1) also found in M. eriococci. Phylogenetic analysis highly supported the monophyly of Pteromalidae, Eupelmidae, and Encyrtidae are sister groups. Within Encyrtidae, Metaphycus eriococci and Aenasius arizonensis are close to each other.

Clinical Characteristics and Contemporary Prognosis of Ventricular Septal Rupture Complicating Acute Myocardial Infarction: A Single-Center Experience.

Objectives: Ventricular septal rupture (VSR) is a rare but lethal complication of acute myocardial infarction (AMI). We conducted a retrospective analysis of the clinical characteristics of VSR patients and explored the risk factors for long-term mortality. Methods: In this single-center cohort study, 127 patients diagnosed with post-AMI VSR between May 2012 and April 2019 were included. Demographic, clinical, operative, and outcome data were collected. The 30-day and long-term mortality were outcomes of interest. Cox proportional hazard regression analysis was used to explore the predictors of long-term mortality. Results: The mean age of the VSR cohort was 66.6 ± 8.7 years, 67 (52.8%) were males. Among the 127 patients, 78 patients (61.4%) were medically managed, 31 (24.4%) patients underwent percutaneous transcatheter closure (TCC), and 18 (14.2%) patients received surgical repair. The median follow-up time was 1129 days [interquartile range: 802-2019 days]. The 30-day mortality of the medically managed group, percutaneous TCC group, and surgical management group was 93.6, 22.6, and 11.1%, respectively; and the long-term mortality was 96.2, 25.8, and 22.2%, respectively. VSR repair treatment including surgical management (HR 0.01, 95% CI 0.001-0.09, p < 0.001) and percutaneous TCC (HR 0.09, 95% CI 0.03-0.26, p < 0.001) was associated with a better prognosis, and cardiogenic shock (CS) (HR 9.30, 95% CI 3.38-25.62, p < 0.001) was an independent risk factor of long-term mortality. Conclusions: The prognosis of VSR patients without operative management remains poor, especially in those complicated with CS. Timely and improved surgery treatment is needed for better outcomes in VSR patients.

Sequencing and analysis of the complete mitochondrial genome of Habrobracon hebetor (Hymenoptera: Braconidae).

We determined the complete mitochondrial genome sequence of Habrobracon hebetor (Say). The complete mitogenome sequence of H. hebetor was observed to be a circular molecule 15,708 bp long and consists of 13 protein-coding genes (PCG), 2 ribosomal RNA (rRNA) genes, and 22 transfer RNA (tRNA) genes (GenBank accession no. MN842279). This nucleotide composition is biased toward adenine and thymine (85.2% A + T). The A + T-rich region is found between trnM and trnQ, and this entire region was 864 bp long.

Deubiquitinase Ubiquitin-Specific Protease 10 Deficiency Regulates Sirt6 signaling and Exacerbates Cardiac Hypertrophy.

Background Cardiac hypertrophy (CH) is a physiological response that compensates for blood pressure overload. Under pathological conditions, hypertrophy can progress to heart failure as a consequence of the disorganized growth of cardiomyocytes and cardiac tissue. USP10 (ubiquitin-specific protease 10) is a member of the ubiquitin-specific protease family of cysteine proteases, which are involved in viral infection, oxidative stress, lipid drop formation, and heat shock. However, the role of USP10 in CH remains largely unclear. Here, we investigated the roles of USP10 in CH. Methods and Results Cardiac-specific USP10 knockout (USP10-CKO) mice and USP10-transgenic (USP10-TG) mice were used to examined the role of USP10 in CH following aortic banding. The specific functions of USP10 were further examined in isolated cardiomyocytes. USP10 expression was increased in murine hypertrophic hearts following aortic banding and in isolated cardiomyocytes in response to hypertrophic agonist. Mice deficient in USP10 in the heart exhibited exaggerated cardiac hypertrophy and fibrosis following pressure overload stress, which resulted in worsening of cardiac contractile function. In contrast, cardiac overexpression of USP10 protected against pressure overload-induced maladaptive CH. Mechanistically, we demonstrated that USP10 activation and interaction with Sirt6 in response to angiotensin II led to a marked increase in the ubiquitination of Sirt6 and resulted in Akt signaling downregulation and attenuation of cardiomyocyte hypertrophy. Accordingly, inactivation of USP10 reduced Sirt6 abundance and stability and diminished Sirt6-induced downstream signaling in cardiomyocytes. Conclusions USP10 functions as a Sirt6 deubiquitinase that induces cardiac myocyte hypertrophy and triggers maladaptive CH.

Myotubularin-related protein 14 suppresses cardiac hypertrophy by inhibiting Akt.

Cardiac hypertrophy (CH) is an independent risk factor for many cardiovascular diseases, and is one of the primary causes of morbidity and mortality in elderly people. Pathological CH involves excessive protein synthesis, increased cardiomyocyte size, and ultimately the development of heart failure. Myotubularin-related protein 14 (MTMR14) is a member of the myotubularin (MTM)-related protein family, which is involved in apoptosis, aging, inflammation, and autophagy. However, its exact function in CH is still unclear. Herein, we investigated the roles of MTMR14 in CH. We show that MTMR14 expression was increased in hypertrophic mouse hearts. Mice deficient in heart MTMR14 exhibited an aggravated aortic-banding (AB)-induced CH phenotype. In contrast, MTMR14 overexpression prevented pressure overload-induced hypertrophy. At the molecular level, prevention of CH in the absence of MTMR14 involved elevations in Akt pathway components, which are key elements that regulate apoptosis and cell proliferation. These results demonstrate that MTMR14 is a new molecular target for the treatment of CH.