E3 ligase TRIM72 negatively regulates myogenesis by IRS-1 ubiquitination

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1 E3 ligase negatively regulates myogenesis by IRS-1 ubiquitination Young-Gyu Ko College of Life Science and Biotechnology Korea University MyHC immunofluorescence

2 Lipid rafts are plasma membrane compartments composed of cholesterol and glycosphingolipids.

3 Insulin action through lipid rafts Signaling molecules found in lipid rafts; IR, IRS, Grb2, Sos, Ras, PI-3-K, TC10, Cbl, CAP, and GLUT4

4 Identification of novel signaling molecules by lipid raft proteome 지질래프트는신호전달물질을농축하고있어서새로운신호전달물질의동정에매우유리

5 Functional proteomics of lipid rafts

6 Functional proteomics of lipid rafts The function of Cell Death Differ, 2010 Lipid raft proteome papers in our lab, gc1qr, surface OXPHOS JBC, 2011; a paper of the week Expert Rev. Proteomics, 2010 CDD, 2010 BBRC, 2010 Proteomics, 2010; cover paper Proteomics, 2009; issue paper Proteomics, 2006; cover paper, 51 citations Diabetologia, 2006; 82 citations EMM, 2004; 66 citations Proteomics, 2004; 30 citations Proteomics, 2004; 108 citations

7 C2C12 Myogenesis Myoblasts Myotubes Myosin Heavy Chain

8 is found in the lipid rafts of C2C12 myotubes. Lee et al., CDD, 2010

9 gene analysis Myoblasts Myotubes Tripartite Motif (TRIM) E3 ligase activity SPla and RYanodine receptor domain Lee et al., CDD, 2010

10 is specifically expressed in skeletal and cardiac muscle 4.4 Kb 2.4 Kb Cav-3 Lee et al., CDD, 2010

11 is highly expressed during C2C12 myogenesis days after differentiation Cav-3 Cav-3 Myogenin Myogenin MyoD MHC MHC Actin Myostatin MyoD Myf5 IRS-1 Coomasie Staining Lee et al., CDD, 2010

12 is a myogenesis inhibitor Lee et al., CDD, 2010

13 What is a molecular target of in IGF signaling?

14 blocks Akt activation in IGF signaling. Ad-EV Ad Si-Con Si mins after IGF activation p-akt IGF Akt IGFR p-mapk IRS-1 MAPK PI-3-K Myoblast Myotube Actin p-akt mtor Hypertrophy Lee et al., CDD, 2010

15 supresses IRS-1 phosphorylation by IGF mins after IGF activation Ad-EV Ad-TRIM Ad-EV Ad-TRIM Ad-EV Ad-TRIM Si-Con Si-TRIM Si-Con Si-TRIM Si-Con Si-TRIM c pakt Akt IP, IGFR; IB, ptyr IP: IRS-1; IB, ptyr IGF IGFR IRS-1 IP: IRS-1; IB, IGFR PI-3-K IP: IRS-1; IB, PI-3K p-akt Myotube Myoblast IP: IGFR; IB, IGFR IP: IRS-1; IB, IRS-1 mtor Hypertrophy Lee et al., CDD, 2010

16 Molecular association of with IRS-1 WCL Mock Ab mins after IGF activation IP: anti-irs1 IRS-1 IGF IGFR IP: anti-cemi IRS-1 IRS-1 PI-3-K p-akt mtor Hypertrophy Lee et al., CDD, 2010

17 negatively regulates myogenesis via targeting IRS-1. Lee et al., CDD, 2010

18 E3 ligase activity??? Protein Ubiquitination

19 Ring Finger domain of Consensus Sequence of Ring Finger Domain, Zn 2+ binding site CX 2 CX (9-39) CX (1-3) HX (2-3) C/HX 2 CX (4-48) CX 2 C sequence MSAAPGLLHQELSCPLCLQLFDAPVTAECGHSFCRACLGRVAGEPAADGTVLC PCCQAPTRPQALSTNLQLARLVEGLAQVPQGHCEEHLDPLSIYCEQDRALVCGV CASLGSHRGHRLLPAAEAHARLKTQLPQQKLQLQEACMRKEKSVAVLEHQLVV EETVRQFRGAVGEQLGKMRVFLAALEGSLDCEAERVRGEAGVALRRELGSLNS YLEQLRQMEKVLEEVADKPQTEFLMKYCLVTSRLQKILAESPPPARLDIQLPIISD DFKFQVWRKMFRALMPALEELTFDPSSAHPSLVVSSSGRRVECSEQKAPPAGED PRQFDKAVAVVAHQQLSEGEHYWEVDVGDKPRWALGVIAAEAPRRGRLHAVPS QGLWLLGLREGKILEAHVEAKEPRALRSPERRPTRIGLYLSFGDGVLSFYDASD ADALVPLFAFHERLPRPVYPFFDVCWHDKGKNAQPLLLVGPEGAEA C 14 C 17 C 29 H 31 C 34 C 37 C 53 C 56 Zn 2+ Zn 2+ C14A mutant? RING mutant?

20 RING domain of is essential for the negative regulation of myogenesis. AD-LacZ AD-TRIM AD-C14A AD- R 20 µm Myogenic index (%) ** * : < 0.01 ** : < 0.05 * ** MyHC Caveolin-3 Myogenin IRS-1 Actin C2C12 myotubes

21 RING domain of is required for the negative regulation of IGF signaling IGF-1 (min) pakt Akt perk1/2 WCL Erk1/2 IRS-1 Actin IP:IRS-1, IB:pY IGF IGFR IRS-1 PI-3-K IP:IRS-1, IB:IRS-1 IP:IRS-1, IB:PI3K IP:IGFR, IB:IRS-1 IP:IGFR, IB:pY IB:IGFR, IB:IGFR p-akt mtor Hypertrophy C2C12 myoblasts

22 RING domain-lacking mutants work as dominant negative forms of endogenous Myc-TRIM Flag-TRIM Flag-C14A Myc-TRIM Flag- R IP: Myc, IB: Myc IP: Myc, IB: Myc IP: Myc, IB: Flag IP: Myc, IB: Flag IP: Flag, IB: Flag IP: Flag, IB: Flag IP: Flag, IB: Myc IP: Flag, IB: Myc IB: Myc (WCL) IB: Myc (WCL) IB: Flag (WCL) IB: Flag (WCL) oligomerization HEK 293 cells

23 RING domain does not prevent binding of to IRS-1 Differentiation days A IRS-1 mrna Actin mrna Flag-IRS-1 Myogenin MyHC Cav-3 IP:Flag, IB:Flag IP:Flag, IB:HA IP:HA, IB:Flag IP:HA, IB:HA IRS-1 IB:Flag (WCL) Actin IB:HA (WCL) C2C12 cells HEK 293 cells

24 RING domain of is required for IRS-1 degradation MG132 Flag-hIRS-1 HA-h IB : Flag IB : HA MG MG Flag-hIRS-1 HA-h IB: Flag IB: HA IRS-1 Expression Level (%) Flag-hIRS-1 HA-h MG132 HEK 293 cells

25 RING domain of is required for IRS-1 ubiquitination HA-TRIM HA-C14A HA- R Flag-IRS-1 His-Ub IP, α-flag; IB, α-his IP, α-flag; IB, α-flag IB: α-ha (WCL) IB: α-flag (WCL) In the presence of MG132 HEK 293 cells

26 RING domain of is required for IRS-1 ubiquitination. -MG132 +MG si-control si- IRS-1 IRS-1 IP: α-irs-1 IB: α-ub IP: α-irs-1 IB: α-ub C2C12 Myoblasts IP: α-irs-1 IB: α-irs-1 IP: α-irs-1 IB: α-irs-1 C2C12 Myotubes

27 disruption enhances MyoD-driven myogenesis in MEFs. WT KO Differentiation days MyoD Myogenin Caveolin-3 MyHC IRS-1 Actin Nuclei No WT KO MyoD Caveolin-3 Myogenin MyHC 0 WT KO IRS-1 Actin MyoD-driven myotubes from +/+ and -/- MEFs

28 disruption abolishes IRS-1 ubiquitination in MyoD-driven myotubes of MEFs MG132 WT KO WT KO IRS-1 IP: α-irs-1 IB: α-ub IP: α-irs-1 IB: α-irs-1 MyoD-driven myotubes from +/+ and -/- MEFs

29 E3 ligase activity??? Protein Ubiquitination

30 UbcH2 mrna and protein are increased during C2C12 myogenesis Differentiation days UbcH2 UbcH3 UbcH5b UbcH6 UbcH2/GAPDH ** * Real-time PCR UbcH7 UbcH8 UbcH10 Ubc Differentiation days Differentiation days UBCH2 Ubc13 Cav-3 Mgn MyHC IRS1 MyoD Cav-3 GAPDH Actin

31 Molecular association of with UbcH2 IP:MBP IB:His IB:MBP IB:His Purified and E2 enzymes In vitro binding assay

32 Molecular association of with UbcH Flag-UbcH Myc-WT Flag Myc Myc Flag Flag Myc WCL IP:IMyc IP:IFlag UbcH2 UbcH2 IP: IP: UbcH2 Exogenous IP in 293 cells Endogenous IP in C2C12 myotubes

33 UbcH2 knockdown enhances myogenesis by inhibiting IRS-1 ubiquitination. Si-control Si-UbcH Si-control Si-UbcH2 Myogenic index (%) * UbcH2 MyHC Cav-3 Mgn IRS-1 UbcH2 IRS-1 WCL Ubiquitin IRS-1 IP:IRS-1 Actin C2C12 myotubes

34 inhibition of myogenesis is released by UbcH2 knockdown Si-control HA- Si-UbcH2 HA si-control HA- si-ubch2 HA- The number of nucleus In HA-positive cells MyHC HA DAPI C2C12 myotubes

35 is highly expressed in soleus muscle. soleus gastrocnemius Color Red muscle White muscle Size Smaller Larger Fatigue Resistant High Sensitive Low Jung and Ko, BBRC, 2010

36 Skeletal muscle size is increased in -disrupted mice * <0.05 Weight (mg) WT WT KO KO Percentage (%) WT KO 2.0 Cross Sectioned Area (mm 2 ) Mouse soleus muscle

37 IRS-1 expression level is elevated in TRIM-disrupted skeletal muscle WT - + KO - + Insulin Insulin (min) pakt Akt perk Erk Actin IRS-1 pakt Akt perk ERK Actin C2C12 Myoblasts py IRS-1 IP:IRS-1 Mouse soleus muscle

38 is a therapeutic target for type 2 diabetes Plasma glucose (mg/dl) Glucose tolerance test WT KO *p<0.05 * * Time (min) Plasma glucose (% reduction) 120 * Insulin tolerance test *p<0.05 * * WT KO Time (min) High fat diet-fed mice

39 E3 ligase negatively regulates myogenesis by IRS-1 ubiquitination. by Ub

40 Suggestion; is a negative muscle size regulator.

41 Korea University Lab of Cell Signal Transduction Dr. Jae-Sung Yi Dr. Chang-Seok Lee Dr. Young-Mi Ham Miss Na-Rae Lee Ms. Nga Nguyen Mr. Jing Hong Mr. June-Seop Lee Mr. Jeong-Woo Lee Mr. Dong-Min Yoo

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