bims-obesme Biomed News
on Obesity metabolism
Issue of 2024–04–21
thirteen papers selected by
Xiong Weng, University of Edinburgh
  1. IL-33 regulates adipogenesis via Wnt/β-catenin/PPAR-γ signaling pathway in preadipocytes.
  2. Mechanistic insights into the role of USP14 in adipose tissue macrophage recruitment and insulin resistance in obesity.
  3. Cullin 3 RING E3 ligase inactivation causes NRF2-dependent NADH reductive stress, hepatic lipodystrophy, and systemic insulin resistance.
  4. Fibroblast Growth Factor 19 in Alcohol-Associated Liver Disease: Bile Acids and Dysbiosis and Inflammation, Oh My!
  5. METTL14 downregulation drives S100A4+ monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression.
  6. Activation of hepatic acetyl-CoA carboxylase by S-nitrosylation in response to diet.
  7. Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms.
  8. The role of STAT3/VAV3 in glucolipid metabolism during the development of HFD-induced MAFLD.
  9. Regulated regeneration of adipose tissue in lipodystrophic Agpat2-null mice partially ameliorates hepatic steatosis.
  10. Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity.
  11. LRP1 in GABAergic neurons is a key link between obesity and memory function.
  12. The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction.
  13. Threonine phosphorylation of STAT1 restricts interferon signaling and promotes innate inflammatory responses.
  1. J Transl Med. 2024 Apr 17. 22(1): 363
    IL-33 regulates adipogenesis via Wnt/β-catenin/PPAR-γ signaling pathway in preadipocytes.
    Danning Xu, Siqi Zhuang, Hongzhi Chen, Mengjie Jiang, Ping Jiang, Qian Wang, Xuemei Wang, Ruohong Chen, Haoneng Tang, Lingli Tang.
      Interleukin-33 (IL-33), an emerging cytokine within the IL-1 family, assumes a pivotal function in the control of obesity. However, the specific mechanism of its regulation of obesity formation remains unclear. In this study, we found that the expression level of IL-33 increased in visceral adipose tissue in mice fed with a high-fat diet (HFD) compared with that in mice fed with a normal diet (ND). In vitro, we also found the expression level of IL-33 was upregulated during the adipogenesis of 3T3-L1 cells. Functional test results showed that knockdown of IL-33 in 3T3-L1 cells differentiation could promote the accumulation of lipid droplets, the content of triglyceride and the expression of adipogenic-related genes (i.e. PPAR-γ, C/EBPα, FABP4, LPL, Adipoq and CD36). In contrast, overexpression of IL-33 inhibits adipogenic differentiation. Meanwhile, the above tests were repeated after over-differentiation of 3T3-L1 cells induced by oleic acid, and the results showed that IL-33 played a more significant role in the regulation of adipogenesis. To explore the mechanism, transcriptome sequencing was performed and results showed that IL-33 regulated the PPAR signaling pathway in 3T3-L1 cells. Further, Western blot and confocal microscopy showed that the inhibition of IL-33 could promote PPAR-γ expression by inhibiting the Wnt/β-catenin signal in 3T3-L1 cells. This study demonstrated that IL-33 was an important regulator of preadipocyte differentiation and inhibited adipogenesis by regulating the Wnt/β-catenin/PPAR-γ signaling pathway, which provided a new insight for further research on IL-33 as a new intervention target for metabolic disorders.
    Keywords:  3T3-L1 cells; Adipogenesis; Interleukin-33; Obesity; PPAR gamma; Wnt/β-catenin
    DOI:  https://doi.org/10.1186/s12967-024-05180-0
  2. Int J Biol Macromol. 2024 Apr 15. pii: S0141-8130(24)02450-4. [Epub ahead of print]267(Pt 2): 131645
    Mechanistic insights into the role of USP14 in adipose tissue macrophage recruitment and insulin resistance in obesity.
    Dongqin Wei, Xin Tian, Zeyu Ren, Zunhai Liu, Chao Sun.
      Diet-induced obesity can cause metabolic syndromes. The critical link in disease progression is adipose tissue macrophage (ATM) recruitment, which drives low-level inflammation, triggering adipocyte dysfunction. It is unclear whether ubiquitin-specific proteinase 14 (USP14) affects metabolic disorders by mediating adipose tissue inflammation. In the present study, we showed that USP14 is highly expressed in ATMs of obese human patients and diet-induced obese mice. Mouse USP14 overexpression aggravated obesity-related insulin resistance by increasing the levels of pro-inflammatory ATMs, leading to adipose tissue inflammation, excessive lipid accumulation, and hepatic steatosis. In contrast, USP14 knockdown in adipose tissues alleviated the phenotypes induced by a high-fat diet. Co-culture experiments showed that USP14 deficiency in macrophages led to decreased adipocyte lipid deposition and enhanced insulin sensitivity, suggesting that USP14 plays an important role in ATMs. Mechanistically, USP14 interacted with TNF receptor-associated 6, preventing K48-linked ubiquitination as well as proteasome degradation, leading to increased pro-inflammatory polarization of macrophages. In contrast, the pharmacological inhibition of USP14 significantly ameliorated diet-induced hyperlipidemia and insulin resistance in mice. Our results demonstrated that macrophage USP14 restriction constitutes a key constraint on the pro-inflammatory M1 phenotype, thereby inhibiting obesity-related metabolic diseases.
    Keywords:  Adipose tissue macrophage; Insulin resistance; USP14
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.131645
  3. Proc Natl Acad Sci U S A. 2024 Apr 23. 121(17): e2320934121
    Cullin 3 RING E3 ligase inactivation causes NRF2-dependent NADH reductive stress, hepatic lipodystrophy, and systemic insulin resistance.
    Lijie Gu, Yanhong Du, Jianglei Chen, Mohammad Nazmul Hasan, Yung Dai Clayton, David J Matye, Jacob E Friedman, Tiangang Li.
      Cullin RING E3 ligases (CRL) have emerged as key regulators of disease-modifying pathways and therapeutic targets. Cullin3 (Cul3)-containing CRL (CRL3) has been implicated in regulating hepatic insulin and oxidative stress signaling. However, CRL3 function in liver pathophysiology is poorly defined. Here, we report that hepatocyte Cul3 knockout results in rapid resolution of steatosis in obese mice. However, the remarkable resistance of hepatocyte Cul3 knockout mice to developing steatosis does not lead to overall metabolic improvement but causes systemic metabolic disturbances. Liver transcriptomics analysis identifies that CRL3 inactivation causes persistent activation of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant defense pathway, which also reprograms the lipid transcriptional network to prevent TG storage. Furthermore, global metabolomics reveals that NRF2 activation induces numerous NAD+-consuming aldehyde dehydrogenases to increase the cellular NADH/NAD+ ratio, a redox imbalance termed NADH reductive stress that inhibits the glycolysis-citrate-lipogenesis axis in Cul3 knockout livers. As a result, this NRF2-induced cellular lipid storage defect promotes hepatic ceramide accumulation, elevates circulating fatty acids, and worsens systemic insulin resistance in a vicious cycle. Hepatic lipid accumulation is restored, and liver injury and hyperglycemia are attenuated when NRF2 activation and NADH reductive stress are abolished in hepatocyte Cul3/Nrf2 double-knockout mice. The resistance to hepatic steatosis, hyperglycemia, and NADH reductive stress are observed in hepatocyte Keap1 knockout mice with NRF2 activation. In summary, our study defines a critical role of CRL3 in hepatic metabolic regulation and demonstrates that the CRL3 downstream NRF2 overactivation causes hepatic metabolic maladaptation to obesity and insulin resistance.
    Keywords:  cullin; fatty liver; insulin resistance; neddylation; reductive stress
    DOI:  https://doi.org/10.1073/pnas.2320934121
  4. Cell Mol Gastroenterol Hepatol. 2024 Apr 15. pii: S2352-345X(24)00069-9. [Epub ahead of print]
    Fibroblast Growth Factor 19 in Alcohol-Associated Liver Disease: Bile Acids and Dysbiosis and Inflammation, Oh My!
    Lindsey Kennedy.
      
    DOI:  https://doi.org/10.1016/j.jcmgh.2024.03.014
  5. Signal Transduct Target Ther. 2024 Apr 17. 9(1): 91
    METTL14 downregulation drives S100A4+ monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression.
    Yue-Fan Wang, Wen-Li Zhang, Zhi-Xuan Li, Yue Liu, Jian Tan, Hao-Zan Yin, Zhi-Chao Zhang, Xian-Jie Piao, Min-Hao Ruan, Zhi-Hui Dai, Si-Jie Wang, Chen-Yang Mu, Ji-Hang Yuan, Shu-Han Sun, Hui Liu, Fu Yang.
      Without intervention, a considerable proportion of patients with metabolism-associated fatty liver disease (MAFLD) will progress from simple steatosis to metabolism-associated steatohepatitis (MASH), liver fibrosis, and even hepatocellular carcinoma. However, the molecular mechanisms that control progressive MAFLD have yet to be fully determined. Here, we unraveled that the expression of the N6-methyladenosine (m6A) methyltransferase METTL14 is remarkably downregulated in the livers of both patients and several murine models of MAFLD, whereas hepatocyte-specific depletion of this methyltransferase aggravated lipid accumulation, liver injury, and fibrosis. Conversely, hepatic Mettl14 overexpression alleviated the above pathophysiological changes in mice fed on a high-fat diet (HFD). Notably, in vivo and in vitro mechanistic studies indicated that METTL14 downregulation decreased the level of GLS2 by affecting the translation efficiency mediated by YTHDF1 in an m6A-depedent manner, which might help to form an oxidative stress microenvironment and accordingly recruit Cx3cr1+Ccr2+ monocyte-derived macrophages (Mo-macs). In detail, Cx3cr1+Ccr2+ Mo-macs can be categorized into M1-like macrophages and S100A4-positive macrophages and then further activate hepatic stellate cells (HSCs) to promote liver fibrosis. Further experiments revealed that CX3CR1 can activate the transcription of S100A4 via CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1+Ccr2+ Mo-macs. Restoration of METTL14 or GLS2, or interfering with this signal transduction pathway such as inhibiting MyD88 could ameliorate liver injuries and fibrosis. Taken together, these findings indicate potential therapies for the treatment of MAFLD progression.
    DOI:  https://doi.org/10.1038/s41392-024-01797-1
  6. J Lipid Res. 2024 Apr 17. pii: S0022-2275(24)00047-6. [Epub ahead of print] 100542
    Activation of hepatic acetyl-CoA carboxylase by S-nitrosylation in response to diet.
    Nicholas M Venetos, Colin T Stomberski, Zhaoxia Qian, Richard T Premont, Jonathan S Stamler.
      Nitric oxide (NO), produced primarily by nitric oxide synthase (NOS) enzymes, is known to influence energy metabolism by stimulating fat uptake and oxidation. The effects of NO on de novo lipogenesis, however, are less clear. Here we demonstrate that hepatic expression of eNOS is reduced following prolonged administration of a hypercaloric high-fat diet. This results in marked reduction in the amount of S-nitrosylation of liver proteins including notably Acetyl-CoA Carboxylase (ACC), the rate-limiting enzyme in de novo lipogenesis. We further show that ACC S-nitrosylation markedly increases enzymatic activity. Diminished eNOS expression and ACC S-nitrosylation may thus represent a physiological adaptation to caloric excess by constraining lipogenesis. Our findings demonstrate that S-nitrosylation of liver proteins is subject to dietary control and suggest that de novo lipogenesis is coupled to dietary and metabolic conditions through ACC S-nitrosylation.
    Keywords:  Acetyl-CoA Carboxylase; Cell signaling; Dietary fat; Lipogenesis; Liver; S-nitrosylation; Triglycerides
    DOI:  https://doi.org/10.1016/j.jlr.2024.100542
  7. Metabolism. 2024 Apr 15. pii: S0026-0495(24)00141-0. [Epub ahead of print] 155915
    Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms.
    Michael M Richter, Ida M Kemp, Sara Heebøll, Marie Winther-Sørensen, Sasha A S Kjeldsen, Nicole J Jensen, Janus D Nybing, Frederik H Linden, Erik Høgh-Schmidt, Mikael P Boesen, Sten Madsbad, Frank Vinholt Schiødt, Kirsten Nørgaard, Signe Schmidt, Lise Lotte Gluud, Steen B Haugaard, Jens J Holst, Søren Nielsen, Jørgen Rungby, Nicolai J Wewer Albrechtsen.
       INTRODUCTION: Glucagon receptor agonism is currently explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The metabolic effects of glucagon receptor agonism may in part be mediated by increases in circulating levels of Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor 15 (GDF15). The effect of glucagon agonism on FGF21 and GDF15 levels remains uncertain, especially in the context of elevated insulin levels commonly observed in metabolic diseases.
    METHODS: We investigated the effect of a single bolus of glucagon and a continuous infusion of glucagon on plasma concentrations of FGF21 and GDF15 in conditions of endogenous low or high insulin levels. The studies included individuals with overweight with and without MASLD, healthy controls (CON) and individuals with type 1 diabetes (T1D). The direct effect of glucagon on FGF21 and GDF15 was evaluated using our in-house developed isolated perfused mouse liver model.
    RESULTS: FGF21 and GDF15 correlated with plasma levels of insulin, but not glucagon, and their secretion were highly increased in MASLD compared with CON and T1D. Furthermore, FGF21 levels in individuals with overweight with or without MASLD did not increase after glucagon stimulation when insulin levels were kept constant. FGF21 and GDF15 levels were unaffected by direct stimulation with glucagon in the isolated perfused mouse liver.
    CONCLUSION: The glucagon-induced secretion of FGF21 and GDF15 are augmented in MASLD and may depend on insulin. Thus, glucagon receptor agonism may augment its metabolic benefits in patients with MASLD through enhanced secretion of FGF21 and GDF15.
    Keywords:  Hepatic steatosis; Hepatokines; Insulin; Mouse liver perfusion; Type 1 diabetes
    DOI:  https://doi.org/10.1016/j.metabol.2024.155915
  8. Int J Biol Sci. 2024 ;20(6): 2027-2043
    The role of STAT3/VAV3 in glucolipid metabolism during the development of HFD-induced MAFLD.
    Yue Jiang, Pengcheng Luo, Yu Cao, Dewei Peng, Shengqi Huo, Junyi Guo, Moran Wang, Wei Shi, Cuntai Zhang, Sheng Li, Li Lin, Jiagao Lv.
      Metabolic-associated fatty liver disease (MAFLD) is a globally prevalent chronic hepatic disease. Previous studies have indicated that the activation of the signal transducer and activator of transcription3 (STAT3) plays a vital role in MAFLD progression at the very beginning. However, the specific association between STAT3 and abnormal hepatic metabolism remains unclear. In this study, activated inflammation was observed to induce abnormal glucolipid metabolic disorders in the hepatic tissues of high-fat diet (HFD)-fed ApoE-/- mice. Furthermore, we found that the activation of STAT3 induced by HFD might function as a transcriptional factor to suppress the expression of VAV3, which might participate in intracellular glucolipid metabolism and the regulation of glucose transporter 4 (GLUT4) storage vesicle traffic in the development of MAFLD both in vitro and in vivo. We verified that VAV3 deficiency could retard the GLUT4 membrane translocation and impair the glucose homeostasis. Additionally, VAV3 participates in cholesterol metabolism in hepatocytes, eventually resulting in the accumulation of intracellular cholesterol. Moreover, rAAV8-TBG-VAV3 was conducted to restore the expression of VAV3 in HFD-fed ApoE-/- mice. VAV3 overexpression was observed to improve glucose homeostasis as well as attenuate hepatic cholesterol accumulation in vivo. In conclusion, the STAT3/VAV3 signaling pathway might play a significant role in MAFLD by regulating glucose and cholesterol metabolism, and VAV3 might be a potential therapeutic strategy which could consequently ameliorate MAFLD.
    Keywords:  GLUT4; MAFLD; STAT3; VAV3; glucolipid metabolism
    DOI:  https://doi.org/10.7150/ijbs.86465
  9. iScience. 2024 Apr 19. 27(4): 109517
    Regulated regeneration of adipose tissue in lipodystrophic Agpat2-null mice partially ameliorates hepatic steatosis.
    Anil K Agarwal, Katie Tunison, Jay D Horton, Abhimanyu Garg.
      Both humans and mice with congenital generalized lipodystrophy due to AGPAT2 deficiency develop diabetes mellitus, insulin resistance, and hepatic steatosis, which have been attributed to the near total loss of adipose tissue (AT). Here, we show that regulated AT regeneration in doxycycline (dox)-fed Tg-AT-hAGPAT2;mAgpat2-/- mice partially ameliorates hepatic steatosis at 12 weeks of age and causes reduced expression of genes involved in hepatic de novo lipogenesis despite partial (∼30-50%) AT regeneration compared to that in wild-type mice. Compared to chow-fed Tg-AT-hAGPAT2;mAgpat2-/- mice, those fed dox diet had markedly reduced serum insulin levels, suggesting an improvement in insulin resistance. Interestingly, the fasting plasma glucose levels in dox-fed Tg-AT-hAGPAT2;mAgpat2-/- mice were no different than those in chow-fed wild-type mice. Indirect calorimetry revealed normalization in the energy balance of dox-fed Tg-AT-hAGPAT2;mAgpat2-/- mice compared to that in chow-fed mice. This study's findings suggest that partial AT regeneration in lipodystrophic mice can ameliorate metabolic derangements.
    Keywords:  Lipid; Pathophysiology; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.109517
  10. Proc Natl Acad Sci U S A. 2024 Apr 23. 121(17): e2322332121
    Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity.
    Yan Q Chen, Ye Yang, Eugene Y Zhen, Thomas P Beyer, Hongxia Li, Yi Wen, Mariam Ehsani, Nicholas Jackson, Katherine Xie, Hyesoo Jung, Julia L Scheithauer, Anni Kumari, Gabriel Birrane, Anna M Russell, Deepa Balasubramaniam, Zhongping Liao, Robert W Siegel, Yuewei Qian, Michael Ploug, Stephen G Young, Robert J Konrad.
      Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its capacity to inhibit lipoprotein lipase (LPL) catalytic activity and its ability to detach LPL from binding sites within capillaries. However, the sequences in APOA5 that are required for suppressing ANGPTL3/8 activity have never been defined. A clue to the identity of those sequences was the presence of severe hypertriglyceridemia in two patients harboring an APOA5 mutation that truncates APOA5 by 35 residues ("APOA5Δ35"). We found that wild-type (WT) human APOA5, but not APOA5Δ35, suppressed ANGPTL3/8's ability to inhibit LPL catalytic activity. To pursue that finding, we prepared a mutant mouse APOA5 protein lacking 40 C-terminal amino acids ("APOA5Δ40"). Mouse WT-APOA5, but not APOA5Δ40, suppressed ANGPTL3/8's capacity to inhibit LPL catalytic activity and sharply reduced plasma TG levels in mice. WT-APOA5, but not APOA5Δ40, increased intracapillary LPL levels and reduced plasma TG levels in Apoa5-/- mice (where TG levels are high and intravascular LPL levels are low). Also, WT-APOA5, but not APOA5Δ40, blocked the ability of ANGPTL3/8 to detach LPL from cultured cells. Finally, an antibody against a synthetic peptide corresponding to the last 26 amino acids of mouse APOA5 reduced intracapillary LPL levels and increased plasma TG levels in WT mice. We conclude that C-terminal sequences in APOA5 are crucial for suppressing ANGPTL3/8 activity in vitro and for regulating intracapillary LPL levels and plasma TG levels in vivo.
    Keywords:  ANGPTL3/8; apolipoprotein AV; lipoprotein lipase; triglycerides
    DOI:  https://doi.org/10.1073/pnas.2322332121
  11. Mol Metab. 2024 Apr 16. pii: S2212-8778(24)00072-3. [Epub ahead of print] 101941
    LRP1 in GABAergic neurons is a key link between obesity and memory function.
    Kellen Cristina da Cruz Rodrigues, Seung Chan Kim, Aaron Aykut Uner, Zhi-Shuai Hou, Jennie Young, Clara Campolim, Ahmet Aydogan, Brendon Chung, Anthony Choi, Won-Mo Yang, Woojin S Kim, Vincent Prevot, Barbara J Caldarone, Hyon Lee, Young-Bum Kim.
       OBJECTIVE: Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood.
    METHODS: Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) underwent behavioral tests for locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. This study evaluated the relationships between behavior and metabolic risk factors and followed the mice at 16 and 32 weeks of age.
    RESULTS: Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. In the spatial Y-maze test, Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice showed a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice during the contextual and cued fear conditioning tests. These effects were accompanied by increased neuronal necrosis and satellitosis in the hippocampus. Importantly, the distance and duration in the novel arm, as well as the performance of the reversal water T-maze test, negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. However, in 16-week-old Vgat-Cre; LRP1loxP/loxP mice, there were no differences in the behavioral tests or correlations between metabolic parameters and cognition.
    CONCLUSIONS: Our findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity.
    Keywords:  Behavior; GABAergic neuron; LRP1; Memory; Neurodegeneration; Obesity
    DOI:  https://doi.org/10.1016/j.molmet.2024.101941
  12. Proc Natl Acad Sci U S A. 2024 Apr 23. 121(17): e2401716121
    The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction.
    Ju Rang Woo, Seung-Hyun Bae, Thomas E Wales, John R Engen, Jongsoon Lee, Hyonchol Jang, SangYoun Park.
      Serine phosphorylations on insulin receptor substrate 1 (IRS-1) by diverse kinases aoccur widely during obesity-, stress-, and inflammation-induced conditions in models of insulin resistance and type 2 diabetes. In this study, we define a region within the human IRS-1, which is directly C-terminal to the PTB domain encompassing numerous serine phosphorylation sites including Ser307 (mouse Ser302) and Ser312 (mouse 307) creating a phosphorylation insulin resistance (PIR) domain. We demonstrate that the IRS-1 PTB-PIR with its unphosphorylated serine residues interacts with the insulin receptor (IR) but loses the IR-binding when they are phosphorylated. Surface plasmon resonance studies further confirm that the PTB-PIR binds stronger to IR than just the PTB domain, and that phosphorylations at Ser307, Ser312, Ser315, and Ser323 within the PIR domain result in abrogating the binding. Insulin-responsive cells containing the mutant IRS-1 with all these four serines changed into glutamates to mimic phosphorylations show decreased levels of phosphorylations in IR, IRS-1, and AKT compared to the wild-type IRS-1. Hydrogen-deuterium exchange mass spectrometry experiments indicating the PIR domain interacting with the N-terminal lobe and the hinge regions of the IR kinase domain further suggest the possibility that the IRS-1 PIR domain protects the IR from the PTP1B-mediated dephosphorylation.
    Keywords:  IRS-1; diabetes; insulin receptor; insulin resistance; serine phosphorylation
    DOI:  https://doi.org/10.1073/pnas.2401716121
  13. Proc Natl Acad Sci U S A. 2024 Apr 23. 121(17): e2402226121
    Threonine phosphorylation of STAT1 restricts interferon signaling and promotes innate inflammatory responses.
    Hozaifa Metwally, Maha M Elbrashy, Tatsuhiko Ozawa, Kazuki Okuyama, Jason T White, Janyerkye Tulyeu, Jonas Nørskov Søndergaard, James Badger Wing, Arisa Muratsu, Hisatake Matsumoto, Masahito Ikawa, Hiroyuki Kishi, Ichiro Taniuchi, Tadamitsu Kishimoto.
      Since its discovery over three decades ago, signal transducer and activator of transcription 1 (STAT1) has been extensively studied as a central mediator for interferons (IFNs) signaling and antiviral defense. Here, using genetic and biochemical assays, we unveil Thr748 as a conserved IFN-independent phosphorylation switch in Stat1, which restricts IFN signaling and promotes innate inflammatory responses following the recognition of the bacterial-derived toxin lipopolysaccharide (LPS). Genetically engineered mice expressing phospho-deficient threonine748-to-alanine (T748A) mutant Stat1 are resistant to LPS-induced lethality. Of note, T748A mice exhibited undisturbed IFN signaling, as well as total expression of Stat1. Further, the T748A point mutation of Stat1 recapitulates the safeguard effect of the genetic ablation of Stat1 following LPS-induced lethality, indicating that the Thr748 phosphorylation contributes inflammatory functionalities of Stat1. Mechanistically, LPS-induced Toll-like receptor 4 endocytosis activates a cell-intrinsic IκB kinase-mediated Thr748 phosphorylation of Stat1, which promotes macrophage inflammatory response while restricting the IFN and anti-inflammatory responses. Depletion of macrophages restores the sensitivity of the T748A mice to LPS-induced lethality. Together, our study indicates a phosphorylation-dependent modular functionality of Stat1 in innate immune responses: IFN phospho-tyrosine dependent and inflammatory phospho-threonine dependent. Better understanding of the Thr748 phosphorylation of Stat1 may uncover advanced pharmacologically targetable molecules and offer better treatment modalities for sepsis, a disease that claims millions of lives annually.
    Keywords:  Stat1; cytokines; phosphorylation; sepsis; threonine
    DOI:  https://doi.org/10.1073/pnas.2402226121
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:26.