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Suresh Subramani

Research

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. Our studies on peroxisome homeostasis examine how peroxisomes are assembled (biogenesis) and destroyed (turnover or pexophagy), as well as the coordination of these two processes within cells. We are also interested in the role of peroxisome biogenesis and turnover proteins in disease states.

Peroxisome biogenesis: We, and others, have focused during the past decade on the genes and proteins involved in the biogenesis of peroxisomes (1). 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 (2). We have also described several sequences called mPTSs, involved in the targeting of peroxisomal membrane proteins (PMPs) (3-5).

We cloned and characterized the PTS1-receptor gene (PEX5) from P. pastoris and from humans (6,7). as well as the P. pastoris PTS2-receptor gene (PEX7), whose human counterpart is mutated in RCDP patients (8). Over a dozen other PEX genes have been characterized in this laboratory (1,2). Recent work has focused on protein-protein interactions among peroxins1, the mechanism, dynamics and regulation of PTS-receptor function (9-11) and on the subcomplexes involved in PTS-receptor docking (12) and in protein translocation across the peroxisomal membrane (13). We are also interested in the role that Pex4p, a ubiquitin-conjugating enzyme, plays in peroxisome biogenesis5.

Current work focuses on the translocation (13) and quality control steps in peroxisomal matrix protein import (11) and on the trafficking of peroxisomal membrane proteins via the endoplasmic reticulum (14).

Peroxisome degradation: Autophagy is a process in which cells eat themselves, especially under starvation conditions, and recycle cellular building blocks such as amino acids, lipids and sugars. Autophagy plays a role in development, aging, neurodegeneration, cell death, cell survival, and innate immunity. While autophagy degrades cargoes non-selectively, it can also be adapted to degrade and recycle selective cargoes. Pexophagy is a turnover pathway in which peroxisomes are selectively degraded by the autophagy machinery in response to specific environmental cues. Other selective autophagy pathways include mitophagy, ribophagy, ER-phagy, micronucleophagy and the Cvt pathway in yeasts (15).

We performed a genetic screen for pexophagy mutants and identified many proteins involved, including the first receptor that tags organelles for autophagic turnover (16). Current work in the laboratory focuses on the mechanisms of action of proteins involved in adapting the core autophagy machinery for pexophagy, and the cellular signaling pathways involved (15).

Publications

  • Subramani, S., Koller, A., Snyder, W.B. (2000). Import of peroxisomal matrix and membrane proteins. Annu. Rev. Biochem. 69: 399-418.
  • Subramani, S. (1998). Components involved in peroxisome import, biogenesis, proliferation, turnover and movement. Physiol. Rev. 78: 171-188.
  • Wiemer, E.A.C., Lüers, G., Faber, K. N., Wenzel, T., Veenhuis, M., Subramani, S. (1996). Isolation and characterization of Pas2p, a peroxisomal membrane protein essential for peroxisome biogenesis in the methylotrophic yeast Pichia pastoris. J. Biol. Chem. 271: 18973-18980.
  • Elgersma, Y., Kwast, L., van den Berg, M., Snyder, W.B., Distel, B., Subramani, S., Tabak, H.F. (1997). Overexpression of Pex15p, a phosphorylated peroxisomal integral membrane protein required for peroxisomal assembly in S. cerevisiae, causes proliferation of the endoplasmic reticulum membrane. EMBO J. 16: 7326-7341.
  • Koller, A., Snyder, W.B., Faber, K.N., Wenzel, T.J., Rangell, L., Keller, G.A., Subramani, S. (1999). Pex22p of Pichia pastoris, essential for peroxisomal matrix protein import, anchors the ubiquitin-conjugating enzyme, Pex4p, on the peroxisomal membrane. J. Cell Biol. 146: 99-112.
  • Terlecky, S.R., Nuttley, W. M., McCollum, D., Sock, E., Subramani, S. (1995). The Pichia pastoris peroxisomal protein, PAS8p, is the receptor for the carboxy-terminal, tripeptide peroxisomal targeting signal. EMBO J. 14: 3627-3634.
  • Wiemer, E. A. C., Nuttley, W. M., Bertolaet, B. L., Li, X., Francke, U., Wheelock, M. J., Anne, U. K., Johnson, K. R., Subramani, S. (1995). The human PTS1 receptor restores peroxisomal protein import in cells from patients with fatal peroxisomal disorders. J. Cell Biol. 130: 51-65.
  • Elgersma, Y., Elgersma-Hooisma, M., Wenzel, T., McCaffery, J.M., Farquhar, M.G., Subramani, S. (1998). A mobile PTS2-receptor for peroxisomal protein import in Pichia pastoris. J. Cell Biol. 140: 807-820.
  • Fransen, M.F., Terlecky, S.R., Subramani, S. (1998). Identification of a human PTS1 receptor docking protein directly required for peroxisomal protein import. Proc. Natl. Acad. Sci. USA 95: 8087-8092.
  • Dammai, V. and Subramani, S. (2001). The human peroxisomal targeting signal receptor, Pex5p, is translocated into the peroxisome matrix and recycled to the cytosol. Cell 105: 187-196.
  • 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).
  • Hazra, P., Suriapranata, I., Snyder, W. and Subramani, S. (2002). Peroxisome remnants in pex3Δ cells and the requirement of Pex3p for interactions between the peroxisomal docking and translocation subcomplexes. Traffic 3: 560-574.
  • Ma, C., Schumann, U., Rayapuram, N., Subramani, S. The peroxisomal matrix import of Pex8p requires only PTS receptors and Pex14p. Mol. Biol. Cell, Aug;20(16):3680-3689. Epub 2009 Jul 1 (2009).
  • Yan, M., Rachubinski, D. A., Joshi, S., Rachubinski, R.A., Subramani, S. Dysferlin domain-containing proteins, Pex30p and Pex31p, localized to two compartments, control the number and size of oleate-induced peroxisomes in Pichia pastoris. Mol. Biol. Cell, Dec 19 [Epub ahead of print] (2007).
  • Manjithaya R, R., Nazarko TY, Farré JC, Subramani S. Molecular mechanism and physiological role of pexophagy, FEBS Lett. 2010 Jan 17 [Epub ahead of print].
  • Farré, J.C., Manjithaya, R., Mathewson, R.D., Subramani, S. PpAtg30 tags peroxisomes for turnover by selective autophagy. Dev. Cell 14: 365-376 (2008).

Biography

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.