De novo formation of peroxisomes
Traditionally, peroxisomes were assumed to be autonomous organelles that proliferate by fission of pre-existing ones. However, recent reports suggested that peroxisomes form de novo from the endoplasmic reticulum1,2. In yeast, de novo peroxisome formation was generally studied in peroxisome-deficient pex3 cells following reintroduction of the PEX3 gene. The basic model prescribed that newly synthesized Pex3 first sorts to the ER, where it concentrates in foci followed by the formation of a nascent peroxisome that pinches off from the ER. Other models include the formation of two3 or multiple4 types of vesicles that form nascent peroxisomes after heterotypic fusion.
Peroxisome biogenesis requires the function of peroxins, which are encoded by PEX genes. Most peroxins are involved in matrix protein import. In their absence, the bulk of the matrix proteins are mislocalized to the cytosol5, even though these cells still contain peroxisomal membrane structures to which peroxisomal membrane proteins (PMPs) are sorted6. Such membrane structures were assumed to be absent in pex3 and pex19 mutant cells and, consequently, it was proposed that Pex3 and Pex19 are involved in peroxisomal membrane formation1,7.
Two main models explain Pex3 and Pex19 function (Fig. 1). In model A, peroxisomes are autonomous organelles that are maintained by growth and fission. Direct insertion of PMPs into peroxisomes depends on Pex3 and Pex198, Pex19 being the chaperone/receptor for PMPs and Pex3 the peroxisomal docking protein for the Pex19-cargo complex. Model B prescribes that PMPs first insert into the ER from which vesicles derive de novo in a Pex3/Pex19-dependent way, thus defining peroxisomes as a branch of the endomembrane system1,2. Both fundamentally different models explain why cells lack peroxisomal membrane structures in the absence of Pex3 or Pex19: in model A, PMPs are instable or mislocalized to the cytosol in pex3 or pex19 cells, whereas in model B, PMPs accumulate at the ER.
Very recently9, our laboratory demonstrated that both models require adaptation. In contrast to the former views, it was found that pre-peroxisomal vesicles (PPV’s) exist in yeast pex3 and pex19 cells. They contain the PMPs Pex13 and Pex14, but lack other PMPS, e.g. Pex10, Pex11 and Pmp47, which require the Pex3/Pex19-machinery for sorting to these membranes (as in model A). These data imply that Pex13 and Pex14 insert into peroxisomal membranes without the assistance of Pex3 and Pex19. Because they do not accumulate at the ER in pex3 cells, also model B is challenged.
The discovery of the PPV’s has unlocked new ways to study peroxisome formation. Currently, our de novo peroxisome formation research focuses on two major questions: How are these PPV’s formed and how do they mature into functional peroxisomes. We aim to answer these questions by combining advanced electron and fluorescence imaging techniques with genetic screening and biochemistry.
1. Hoepfner, D., Schildknegt, D., Braakman, I., Philippsen, P. & Tabak, H.F. (2005). Contribution of the endoplasmic reticulum to peroxisome formation. Cell 122, 85–95
2. Van der Zand, A., Braakman, I. & Tabak, H.F. (2010). Peroxisomal membrane proteins insert into the endoplasmic reticulum. Mol. Biol. Cell 21, 2057–2065
3. Van der Zand, A., Gent, J., Braakman, I. & Tabak, H.F. (2012). Biochemically distinct vesicles from the endoplasmic reticulum fuse to form peroxisomes. Cell 149, 397–409
4. Titorenko, V.I., Chan, H. & Rachubinski, R.A. (2000). Fusion of small peroxisomal vesicles in vitro reconstructs an early step in the in vivo multistep peroxisome assembly pathway of Yarrowia lipolytica. J. Cell Biol. 148, 29–44
5. Platta, H.W., Hagen, S., Reidick, C. & Erdmann, R. (2013). The peroxisomal receptor dislocation pathway: To the exportomer and beyond. Biochimie doi:10.1016/j.biochi.2013.12.009
6. Koek, A., Komori, M., Veenhuis, M. & van der Klei, I.J. (2007). A comparative study of peroxisomal structures in Hansenula polymorpha pex mutants. FEMS Yeast Res. 7, 1126–1133
7. Snyder, W.B., Faber, K.N., Wenzel, T.J., Koller, A., Lüers, G.H., Rangell, L., Keller, G.A. & Subramani, S. (1999). Pex19p interacts with Pex3p and Pex10p and is essential for peroxisome biogenesis in Pichia pastoris. Mol. Biol. Cell 10, 1745–1761
8. Fujiki, Y., Matsuzono, Y., Matsuzaki, T. & Fransen, M. (2006). Import of peroxisomal membrane proteins: the interplay of Pex3p- and Pex19p-mediated interactions. Biochim. Biophys. Acta 1763, 1639–1646
9. Knoops, K., Manivannan, S., Cepińska, M.N., Krikken, A.M., Kram, A.M., Veenhuis, M. & van der Klei, I.J. (2014). Preperoxisomal vesicles can form in the absence of Pex3. J. Cell Biol. 204, 659-668
|Last modified:||18 May 2018 4.45 p.m.|