Suresh Subramani

Research

PEROXISOME 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 in disease states.

Peroxisome biogenesis: Work done in this and other labs has uncovered about 36 peroxins, encoded by PEX genes, involved in peroxisome biogenesis. 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). Work on peroxisome biogenesis is summarized in a review (Farré et al., EMBO Reports, 2018, PMID: 30530632).

Current work focuses on the trafficking of peroxisomal membrane proteins via the endoplasmic reticulum, their budding into pre-peroxisomal vesicles (ppV) and the proteins and mechanisms involved in this ppV budding.

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 key role in development, aging, neurodegeneration, cell death, cell survival, and innate immunity. While autophagy generally degrades cargoes non-selectively, it can also be adapted to degrade and recycle selective cargoes, including organelles and protein aggregates. Pexophagy is a turnover pathway in which redundant, damaged or unnecessary 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. Progress in the field of selective autophagy may be found in a review (Farré et al., Nature Rev. Mol. Cell Biol., 2016, PMC5549613).

Current work focuses on the selective autophagy pathways and the manner in which selective autophagy receptors function.

Select Publications

  • Agrawal, G., Fassas, S. N., Xia, Z., Subramani, S. Distinct requirements for intra-ER sorting and budding of peroxisomal membrane proteins from the endoplasmic reticulum. J. Cell Biol., 212: 335-48 (2016). PMCID: PMC4788575.
  • Zientara-Rytter, K., Subramani, S. Autophagic degradation of peroxisomes in mammals. Biochem. Soc. Trans. 44, 431–440.(2016). PMCID: PMC4958620.
  • Farré, J.C., Subramani, S. Mechanistic insights regarding selective autophagy pathways: lessons from yeast. Nature Reviews Mol. Cell Biol., 17: 537–552. (2016). PMC: PMC5549613.
  • Zientara-Rytter, K., Subramani, S. Role of actin in shaping autophagosomes. Autophagy, 12: 2512-2515 (2016). PMCID: PMC5173263.
  • Kramer, M.H., Farré, J.C., Mitra, K., Yu, M.K., Ono, K., Demchak, B., Licon,, K., Flagg, M., Balakrishnan, R., Cherry, J.M., Subramani, S., Ideker, T. Active Interaction Mapping reveals the hierarchical organization of autophagy. Mol Cell,Evolving 65: 761–774. (2017). PMCID: PMC5439305.
  • Wang, W., Subramani, S. Assays to monitor pexophagy in yeast. In Meth. Enzymology. 588: 413-427. (2017). PMCID: PMC5546006.
  • Agrawal, G., Shang, H.H., Xia, Z.-J., Subramani, S. Functional regions of the peroxin Pex19 necessary for peroxisome biogenesis. J. Biol. Chem. 292: 11547–11560. (2017). PMCID: PMC5500816.
  • Farre, J.-C., Kramer, M., Ideker, T., Subramani, S. Active Interaction Mapping as a tool to elucidate hierarchical functions of biological processes. Autophagy. 13: 1248–1249. (2017). PMCID: PMC5529073.
  • Wang, W., Xia, Z., Farré, J.C., Subramani, S. TRIM37, a novel E3 ligase for PEX5-mediated peroxisomal matrix protein import. J. Cell Biol. 216: 2843-2858. (2017). PMCID: PMC5584156.
  • Wang. W., Subramani, S. Role of PEX5 ubiquitination in maintaining peroxisome dynamics and homeostasis. Cell Cycle, 6: 2037-2045. (2017). PMCID: PMC5731411.
  • Zientara-Rytter, K., Ozeki, K., Nazarko, T.Y., Subramani, S. Pex3 and Atg37 compete to regulate the interaction between the pexophagy receptor, Atg30, and the Hrr25 kinase. Autophagy, 14: 368-384. (2017). PMID: 29260977, PMC journal – in process.
  • Farre, J.-C., Carolino, K., Stasyk, O.V., Stasyk, O. G., Hodzic, Z., Agrawal, G., Till, A., Proietto, M., Cregg, J., Sibirny, A. A., Subramani, S. A new yeast peroxin, Pex36, a functional homologue of mammalian PEX16, functions in the ER–to-peroxisome traffic of peroxisomal membrane proteins. J. Mol. Biol. 429: 3743–3762. (2017). PMCID: PMC5693695.
  • Wang, W., Xia, Z., Farré, J.-C., Subramani, S. TRIM37 deficiency induces autophagy through de-regulating the MTORC1-TFEB axis. Autophagy, 14: 1574-1585. (2018). PMID: 29940807, PMC journal – in process.
  • Zientara-Rytter, K., Subramani, S. AIM/LIR-based fluorescent sensors – new tools to monitor mAtg8 functions. Autophagy, 4: 1074-1078. (2018). PMID: 27068951, PMC journal – in process.

Biography

Suresh Subramani received his Ph.D. from the University California (UC), Berkeley. He joined the faculty at UC San Diego in 1982, after completion of post-doctoral work in the laboratory of Nobel Laureate, Paul Berg, at Stanford University (1979-81). He is the recipient of many honors and awards and has been involved in many leadership roles in academia and in the biotechnology industry. His service to UC includes his role as the Executive Vice Chancellor (2010-16), Assoc. Vice Chancellor (2009-10), Interim Dean (2006-07) and Chair (1999-2000). He is currently a Distinguished Professor (Emeritus), the Global Director of the Tata Institute for Genetics and Society (TIGS, at UC San Diego, USA and at inStem, Bangalore, India) and holds the Tata Chancellor’s Endowed Professorship in Molecular Biology at UC San Diego.