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SP3: Thorsten Pfirrmann - The function of the vertebrate GID-complex in the regulation of cellular energy homeostasis and lifespan extension

Dysregulation of AMPK activity is involved in a variety of age-related metabolic diseases and syndromes like type-2-diabetes (1-4). We discovered and recently published an ATP/AMP-independent regulation mechanism that depends on the ubiquitin-ligase function of the vertebrate GID-complex. Our data show that the GID-complex regulates AMPK activity by ubiquitination. Lack of AMPK ubiquitination leads to constitutive enzyme activation, to a subsequent shift from anabolic to catabolic pathways (branched chain amino acid (BCAA) degradation, beta-oxidation, autophagy), to an increase in organismal lifespan (5) and to a 40% reduction of cellular acetyl-CoA. We hypothesise that the GID-complex is a high potential drug target to affect AMPK activity. To pharmacologically interfere with GID-function in the future we need to obtain a better understanding of the molecular mechanism behind GID-dependent AMPK regulation. We plan to (I) further biochemically characterise AMPK ubiquitination-sites (Ub-sites) by immunoprecipitation and subsequent MS-analytics and (II) study the impact of acetyl-CoA levels on AMPK/GID-activity and organismal lifespan.

 

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2.         Torres VE, Boletta A, Chapman A, Gattone V, Pei Y, Qian Q, et al. Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases. Clin J Am Soc Nephrol. 2010;5(7):1312-29. Epub 2010/05/26. doi: 10.2215/CJN.01360210. PubMed PMID: 20498248.

3.         Hardie DG. AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes. 2013;62(7):2164-72. Epub 2013/06/27. doi: 10.2337/db13-0368. PubMed PMID: 23801715; PubMed Central PMCID: PMCPMC3712072.

4.         Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N, et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci U S A. 2006;103(14):5466-71. Epub 2006/03/29. doi: 10.1073/pnas.0509694103. PubMed PMID: 16567633; PubMed Central PMCID: PMCPMC1459378.

5.         Liu H, Ding J, Kohnlein K, Urban N, Ori A, Villavicencio-Lorini P, et al. The GID ubiquitin ligase complex is a regulator of AMPK activity and organismal lifespan. Autophagy. 2019:1-17. Epub 2019/12/05. doi: 10.1080/15548627.2019.1695399. PubMed PMID: 31795790.