Proteasome and mitochondrial dynamics

Proteasome and mitochondrial dynamics

  • Principal Investigator:
    • Krisztina Tar, Ph.D., assistant professor
  • Lab members:
    • Rita Czinege, MSc. Student
    • Rei Yazaki, MD Student
    • Bernadett Szabó, BSc. Student

The proteasome is the major proteolytic system in the cytoplasm and nuclei of eukaryotic cells. It is required for the maintenance of protein homeostasis through its ability to eliminate damaged and misfolded proteins. Proteasomal activity is subject to tight regulation. To date three types of proteasome activators are known: the conserved regulatory particle (RP/19S/PA700), activators of the PA28 protein family present in higher eukaryotes, and the conserved Blm10/PA200 activator family. The conserved Blm10/PA200 activators bind to the proteasome core particle gate and facilitate peptide turnover. Knowledge of the cellular functions of these proteins is limited. We provided evidence for an additional regulatory function of Blm10-proteasomes in mitochondrial homeostasis. We demonstrated that the fission protein Dnm1 is degraded by the proteasome and that Dnm1 turnover involves the proteasome activator Blm10. Our data indicate that Blm10-proteasomes mediated degradation of Dnm1 is a regulatory mechanism to counteract mitochondrial fission, which provides a cytoprotective function under conditions that induce mitochondrial stress such expression of mutant huntingtin (mHtt) fragments. Impaired Drp1 (the mammalian ortholog of Dnm1) turnover leads to its stabilization, promotes mitochondrial fragmentation and increases its affinity to mHtt aggregates leading eventually to neuronal cell death.

As expected from the importance of Dnm1/Drp1 in eukaryotic cells, its function is subject to tight regulation. They can be grouped into two main categories: post-translational modification such as phosphorylation, and regulated turnover. Our preliminary data provide initial information that the degradation of Dnm1 is triggered by post-translational modification. Our preliminary data also show that loss of BLM10/PA200 leads to increased aggregate/inclusion body (IB) formation of mHtt and mitochondrial fragmentation in yeast and human cells, respectively and that Blm10 is involved clearing mHtt in yeast.

In summary, our data argue for a model in which reduced proteasome function caused by loss of BLM10/PA200 leads to increased stabilization of Dnm1/Drp1 and increased aggregate/IB formation of mHtt. Our hypothesis is that the impaired turnover of Dnm1 in response to BLM10 deletion is conserved and that Drp1 degradation in mammals is mediated by PA200- proteasomes. We propose that regulated Drp1 turnover- mediated by PA200-proteasomes- is required for correct mitochondrial function, especially in response to stress such as expression of mutant Htt. We also propose that the phosphorylation status of Drp1 is crucial for triggering degradation and for correct mitochondrial homeostasis in response to altered kinase signaling under basal condition and/or mitochondrial stress. Lastly, we propose that PA200-proteasome mediated Drp1 and mutant Htt degradation and impaired Drp1 function impact disease progression in Huntington’s disease.
Results of the project may provide novel information on the role of PA200-proteasomes and Drp1 in the progression of Huntington’s disease and might point toward Drp1 as a new target for Huntington’s disease therapy.

Selected publications

  • Yanhua Yao, Scott Tsuchiyama Ciyu Yang, Anne Laure Bulteau, Brett Robison, Chong He, Krisztina Tar, Anahi Potrero, Bertrand Friguet, Brian Kennedy, Marion Schmidt. Proteasomes, Sir2, and Hxk2 form an interconnected aging network that impignes on the AMPK/Snf1-regulated transcriptional repressor Mig1 PloS Genetics accepted in December 2014, IF: 8.167
  • Tar K, Dange T, Yang C, Yao Y, Bulteau AL, Fernandez Salcedo E, Braigen S, Bouillaud F, Finley D, Schmidt M.Proteasomes associated with the Blm10 Activator Protein Antagonize Mitochondrial Fission Through Degradation of the Fission Protein Dnm1. J Biol Chem. 2014 Apr 25;289(17):12145-56 IF: 4.651**
  • M. K. Short, J. P. Hallett, K. Tar, T. Dange, M. Schmidt, I. Willis, P. T. Jubinsky. Pam16, the yeast Magmas ortholog, regulates proliferation through sphingolipid metabolism (PLoS One 2012;7(7):e39428. Epub 2012 Jul 10). IF: 3.73
  • Kruegel U, Robison B, Dange T, Kahlert G, Delaney JR, Kotireddy S, Tsuchiya M, Tsuchiyama S, Murakami CJ, Schleit J, Sutphin G, Carr D, Tar K, Dittmar G, Kaeberlein M, Kennedy BK, Schmidt M. Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae. PLoS Genet. 2011 Sep;7(9). IF: 8.52
  • Lopez AD, Tar K, Kruegel U, Dange T, Ros IG, Schmidt M. Proteasomal degradation of Sfp1 contributes to the repression of ribosome biogenesis during starvation and is mediated by the proteasome activator Blm10. Mol Biol Cell. 2011 Mar;22(5):528-40. IF: 5.98 Joint first author.  
  • Pospisilik JA, Schramek D, Schnidar H, Cronin SJ, Nehme NT, Zhang X, Knauf C, Cani PD, Aumayr K, Todoric J, Bayer M, Haschemi A, Puviindran V, Tar K, Orthofer M, Neely GG, Dietzl G, Manoukian A, Funovics M, Prager G, Wagner O, Ferrandon D, Aberger F, Hui CC, Esterbauer H, Penninger JM. Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate. Cell. 2010 Jan 8;140(1):148-60. IF: 31.96
  • Tar K, Csortos Cs, Czikora I, Olah G, Ma SF, Wadgaonkar R, Gergely P, Garcia JGN, Verin AD: Role of protein phosphatase 2A in the regulation of endothelial cell cytoskeleton structure, J Cell Biochem. Jul 1 2006, 98 (4): 931-953. IF: 3.06
  • Teckchandani AM, Birukova AA, Tar K, Verin AD, Tsygankov AY.The multidomain protooncogenic protein c-Cbl binds to tubulin and stabilizes microtubules Experimental Cell Research, May15 2005, 306 (1): 114-127. IF: 3.56
  • Tar K, Birukova AA, Csortos C, Bakó E, Garcia JG, Verin AD. Phosphatase 2A is involved in endothelial cell microtubule remodeling and barrier regulation. J Cell Biochem. 2004 Jun 1;92(3):534-46. IF: 3.06

Frissítés dátuma: 2017.08.08.