Suresh Subramani
Division of Biological Sciences

Distinguished Professor of Molecular Biology, UCSD

e-mail: ssubramani@ucsd.edu
Lab Homepage: Subramani Lab

Postdoctoral Position information

ORGANELLE HOMEOSTASIS IN YEAST AND HUMANS

       We are interested in the problem of organelle homeostasis, using peroxisomes as the model organelle. Like all other subcellular organelles, peroxisomes and peroxisomal functions are indispensable for human survival. However, one of the reasons we can use this organelle to study homeostasis is that it can be made dispensable at the cellular level. This feature allows us to combine genetics with the other tools of biology to understand the mechanisms involved. Another reason this organelle is attractive for the homeostasis problem is that it can be induced and degraded at will, in response to specific nutritional cues. This is exemplified in the yeast P. pastoris by the induction of peroxisome biogenesis upon switch from glucose to either methanol or oleate, and peroxisome turnover upon shift of the cells from methanol or oleate medium back to glucose.

Peroxisome biogenesis : We, and others, have focused during the past decade on the genes and proteins involved in the biogenesis of peroxisomes1-4. These studies have uncovered about 32 peroxins, encoded by PEX genes, all conspiring to assemble this organelle. Many proteins involved in this process are conserved in evolution from yeast to man, and inactivating mutations in at least half of these peroxins cause fatal human disorders (Zellweger syndrome, rhizomelic chondrodysplasia punctata and infantile Refsum disease).

       We discovered two of the peroxisomal targeting signals (PTSs), called PTS1 and PTS2, involved in the import of proteins into the peroxisomal matrix. We have also described several sequences called mPTSs, involved in the targeting of peroxisomal membrane proteins (PMPs). We cloned and characterized the PTS1-receptor gene (PEX5) from P. pastoris and from humans, as well as the P. pastoris PTS2-receptor gene (PEX7), whose human counterpart is mutated in RCDP patients. About a dozen other PEX genes have been characterized in this laboratory1-4. Recent work has focused on protein-protein interactions among peroxins1,3,4, the mechanism of PTS-receptor function2,4 and on the subcomplexes involved in PTS-receptor docking and in protein translocation across the peroxisomal membrane1. We are also interested in the role that Pex4p, a ubiquitin-conjugating enzyme, plays in peroxisome biogenesis2.

       Current work focuses on the translocation steps in peroxisomal matrix protein, a peroxisome-associated quality-control pathway called RADAR and on the biogenesis of peroxisomal membrane proteins. Both yeast and mammalian cells are used for the analysis of these processes. We also study genes involved in the control of peroxisome size, volume and number5.

Peroxisome degradation : Selective peroxisome turnover (or pexophagy) occurs by autophagic mechanisms involving the lysosome or vacuole in yeast. The vacuole is involved in the receipt and biosynthetic processing of certain proteins directly from the cytosol, via the Cvt pathway. This pathway overlaps substantially with the degradative process of macroautophagy, which is induced by nitrogen starvation, and results in the vacuolar recycling of non-specific cargo6.

      Interestingly, peroxisome turnover in P. pastoris can occur both by macropexophagy, and by an alternative process termed micropexophagy. The former occurs upon shift of P. pastoris from methanol to ethanol, while the latter occurs by switching cells from methanol to glucose. The process of micropexophagy, and the intermediates involved, were elucidated in my lab6. In recent work, we undertook a genetic screen for micropexophagy mutants and identified many genes, making it likely that about 25 genes are involved in the process of pexophagy. Current work in the laboratory focuses on the mechanisms of action of these genes7-10, which include Ser/Thr protein kinases, novel ubiquitin-like conjugation systems, phosphatidyl-inositol-3 kinase and others required for the selectivity of pexophagy.
  1. Rayapuram, N., Subramani, S. The importomer – a peroxisomal membrane complex involved in protein translocation into the peroxisome matrix. Biochim. Biophys. Acta, , Aug 30; [Epub ahead of print] (2006).

  2. Léon, S., Goodman, J.M., Subramani, S. Uniqueness of the mechanism of protein import into the peroxisome matrix: transport of folded, co-factor-bound and oligomeric proteins by shuttling receptors. Biochim. Biophys. Acta, , Aug 30; [Epub ahead of print] (2006).

  3. Zhang, L., Léon, S., Subramani, S. Two independent pathways traffic the intraperoxisomal peroxin Pex8p into peroxisomes: mechanism and evolutionary implications. Mol. Biol. Cell, 17: 690-9 (2006).

  4. Léon, S., Zhang, L., McDonald, H., Yates III, J., Cregg, J. M., Subramani, S. Dynamics of the peroxisomal import cycle of PpPex20p: ubiquitin-dependent localization and regulation. J. Cell Biol., 172: 67-78 (2006).

  5. Yan, M., Rayapuram, N. and Subramani, S. The control of peroxisome number and size during division and proliferation, Curr. Opin. Cell Biol., 14: 376-383 (2005).

  6. Sakai, Y., Koller, A., Rangell, L.K., Keller, G.A., Subramani, S. Peroxisome degradation by microautophagy in Pichia pastoris: identification of specific steps and morphological  intermediates. J. Cell Biol., 141: 625-636 (1998).

  7. Nazarko, T.Y., Polupanov, A.S., Manjithaya, R.R., Subramani, S., Sibirny, A.A. The requirement of sterol glucoside for pexophagy in yeasts is dependent on the species and nature of peroxisome inducers. Mol. Biol. Cell 18: 106-118 (2007).

  8. Farré, J.-C., Vidal, J., Subramani, S. A cytoplasm to vacuole targeting pathway in P. pastoris. Autophagy, 3(3):230-4 (2007).

  9. Nazarko, T.Y., Farré, J.-C., Polupanov, A.S., Sibirny, A.A., Subramani, S. Autophagy-related pathways and specific role of sterol glucoside in yeasts. Autophagy, 3(3):263-5 (2007).

  10. Subramani, S., Farré, J. –C. A  ubiquitin-like protein involved in membrane fusion. Cell 130: 7-9 (2007).
Suresh Subramani received his Ph.D. in Biochemistry from UC Berkeley, working with Dr. Howard Schachman. He was a Jane Coffin Childs Fellow with Dr. Paul Berg at Stanford University. He was the recipient of a Searle Scholar Award, an NCI Research Career Development Award, and a Guggenheim Fellowship. He served as the last Chair of the Department of Biology (1999-2000) prior to its reorganization as a Division, and was the Interim Associate Dean for the Division of Biology (2000-2001). He served as the Interim Dean of the Division of Biological Sciences between 2006-2007. He is a Fellow of the American Acad. Microbiology and the recipient of an NIH MERIT Award. He is currently a Distinguished Professor in the Section of Molecular Biology at UCSD and the Associate Dean for Operations in the Division of Biological Sciences.  Email: ssubramani@ucsd.edu  (last update Oct 8, 2007)