Protein networks and intracellular membrane remodeling
Eukaryotic cells are organized into specialized membrane-bound compartments or organelles, each serving crucial cellular functions. Several transport mechanisms are implicated to maintain the identity as well as the integrated function of the different cellular organelles thereby allowing for survival of the organisms in environments prone to constant changes. Accordingly, organellar dysfunction alters the cellular metabolism and affects the fitness of the cell.
Dynamic alterations of membrane structure are intrinsic to organelle morphogenesis and homeostasis. Among the cellular organelles, peroxisomes are versatile single membrane-bound organelles that enclose essential functions mainly involved with lipid metabolism and degradation of reactive oxygen species. While peroxisomes are dispensable for unicellular organism such as yeast cells, they are essential for the proper development of multicellular organisms. Peroxisomal dysfunction can lead to severe pathological disorders such as adrenoleukodystrophy or the Zellweger syndrome that are typically lethal diseases. Peroxisomes continuously adjust their shape, size, number and protein content according to the metabolic requirements of the cell. Indeed, molecular mechanisms exist that maintain the number and morphology of peroxisomes in the cell through a delicate balance between biogenesis, degradation and inheritance during cell division. The question is what molecular interactions organize such equilibrium?
Several membrane proteins have been shown to participate in the process of peroxisome proliferation in yeast and mammalian cells. We employ several approaches based on quantitative proteomics using metabolic labeling as well as live-cell imaging to analyze the molecular networks involved in the regulation of peroxisome number in the cell. The results of our studies in yeast cells reveal that large membrane proteins complexes physically link peroxisomes to other sub-cellular organelles at specialized contact sites. We currently investigate the formation of these membrane contact sites and their consequence on peroxisome proliferation.
In studies on mammalian cells, using the membrane elongation factor PEX11 and photoactivatable GFP appended with a peroxisomal targeting signal, we recently illustrated the asymmetric inheritance of peroxisomal matrix proteins in the process of peroxisome proliferation a mechanism that might lead to rejuvenation of the peroxisome pool in the cell. Whether the selective degradation of peroxisomes via pexophagy is specifically targeted to “old” organelles is an attractive question that we intend to investigate in details.
Publications since 2006
Huber, Anja; Koch, Johannes; Kragler, Friedrich; Brocard, Cécile; Hartig, Andreas (2012). A Subtle Interplay between Three Pex11 Proteins Shapes de novo Formation and Fission of Peroxisomes. TRAFFIC;1(13):157-167. PMID: 21951626
Johannes Koch, Cécile Brocard (2011). Membrane elongation factors in organelle maintenance: the case of peroxisome proliferation BioMol Concepts;5(2):353-364. PMID: 21984887
Zipor, Gadi; Brocard, Cecile; Gerst, Jeffrey E (2011). Isolation of mRNAs encoding peroxisomal proteins from yeast using a combined cell fractionation and affinity purification procedure. Methods Mol Biol;714:323-33. PMID: 21431750
Koch, Johannes; Pranjic, Kornelija; Huber, Anja; Ellinger, Adolf; Hartig, Andreas; Kragler, Friedrich; Brocard, Cécile (2010). PEX11 family members are membrane elongation factors that coordinate peroxisome proliferation and maintenance. J CELL SCI. PMID: 20826455
Zipor, Gadi; Haim-Vilmovsky, Liora; Gelin-Licht, Rita; Gadir, Noga; Brocard, Cecile; Gerst, Jeffrey E (2009). Localization of mRNAs coding for peroxisomal proteins in the yeast, Saccharomyces cerevisiae. P NATL ACAD SCI USA. PMID: 19903887
Brocard, C; Hartig, A (2007). Peroxins:A Proliferation Romance amongst Supposition and Disposition DYN CELL BIO.
Brocard, Cécile; Hartig, Andreas (2006). Peroxisome targeting signal 1: is it really a simple tripeptide? Biochim Biophys Acta. PMID: 17007944