The peroxisome, an essential subcellular compartment in all eukaryotic cells, is infimately involved in lipid metabolism. Work in multiple model systems has uncovered at least 32 PEX genes encoding peroxins, that play roles In peroxisome biogenesis, morphogenesis (size, volume and number), and inheritance. However, despite this wealth of knowledge regarding the proteins involved, the biochemical functions and mechanisms of action of most peroxins are pooriy understood. Peroxisomal proteins are targeted to the organelle matrix by two peroxisomal targeting signals, PTS1 and PTS2. PTS receptors bound to their cargo interact with the importomer, a complex of peroxisome-membrane-assoclated Pex proteins. The importomer, responsible for peroxisomal matrix protein translocation is comprised of the docking and RING subcomplexes. During the matrix protein import cycle, the receptor-cargo complexes shuttle from the cytosol, interact with the importomer, release cargo in the peroxisome matrix and the receptors then shuttle back to the cytosol, aided by a receptor-recycling subcomplex. Major unanswered questions in the peroxisome biogenesis field relate to the exact nature, function and structure of the unusual peroxisomal translocon which, unlike translocons associated with other subcellular compartments, transports folded and oligomeric proteins across (Aim 1). The evolution of dual matrix protein import pathways and the steps in cargo release and receptor recycling from peroxisomes. Involving the function of Pex8, are critical for an understanding of the import cycle (Aim 2). The recent emergence of a clear involvement of the endoplasmic reficulum (ER) in peroxisome morphogenesis, and even biogenesis, raises important quesfions about the machinery that sorts peroxisomal membrane proteins via the ER and the funcfional role of this pathway in peroxisome growth and division (Aim 3). Finally, we wish to further explore fascinating emerging clues regarding a crosstalk between peroxisome biogenesis, inheritance and turnover (Aim 4). We believe we are uniquely positioned to answer these fundamentally important cell biological quesfions that seriously impact human health and disease.

Public Health Relevance

Impairment of peroxisomal metabolic or biogenesis pathways causes 17, often fatal, human disorders. This proposal will address basic mechanisms involved in peroxisomal matrix and membrane protein assembly, growth and division. By doing so we hope to understand how organelle homeostasis is maintained and how the impairment of these processes can affect human health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK041737-24
Application #
8460880
Study Section
Special Emphasis Panel (NSS)
Program Officer
Haft, Carol R
Project Start
1990-05-10
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
24
Fiscal Year
2013
Total Cost
$566,660
Indirect Cost
$199,890
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Hagstrom, Danielle; Ma, Changle; Guha-Polley, Soumi et al. (2014) The unique degradation pathway of the PTS2 receptor, Pex7, is dependent on the PTS receptor/coreceptor, Pex5 and Pex20. Mol Biol Cell 25:2634-43
Liu, Xueqian; Subramani, Suresh (2013) Unique requirements for mono- and polyubiquitination of the peroxisomal targeting signal co-receptor, Pex20. J Biol Chem 288:7230-40
Ma, Changle; Hagstrom, Danielle; Polley, Soumi Guha et al. (2013) Redox-regulated cargo binding and release by the peroxisomal targeting signal receptor, Pex5. J Biol Chem 288:27220-31
Joshi, Saurabh; Agrawal, Gaurav; Subramani, Suresh (2012) Phosphorylation-dependent Pex11p and Fis1p interaction regulates peroxisome division. Mol Biol Cell 23:1307-15
Agrawal, Gaurav; Joshi, Saurabh; Subramani, Suresh (2011) Cell-free sorting of peroxisomal membrane proteins from the endoplasmic reticulum. Proc Natl Acad Sci U S A 108:9113-8
Ma, Changle; Agrawal, Gaurav; Subramani, Suresh (2011) Peroxisome assembly: matrix and membrane protein biogenesis. J Cell Biol 193:7-16
Manjithaya, Ravi; Anjard, Christophe; Loomis, William F et al. (2010) Unconventional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxisomal functions, and autophagosome formation. J Cell Biol 188:537-46
Ma, Changle; Schumann, Uwe; Rayapuram, Naganand et al. (2009) The peroxisomal matrix import of Pex8p requires only PTS receptors and Pex14p. Mol Biol Cell 20:3680-9
Ma, Changle; Subramani, Suresh (2009) Peroxisome matrix and membrane protein biogenesis. IUBMB Life 61:713-22
Schumann, Uwe; Subramani, Suresh (2008) Special delivery from mitochondria to peroxisomes. Trends Cell Biol 18:253-6

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