Emerging role of the endoplasmic reticulum in peroxisome biogenesis

Abstract

During the past few years, we have witnessed a paradigm shift in our long-standing concept of peroxisome biogenesis. Recent biochemical and morphological studies have revealed a primary role of the endoplasmic reticulum (ER) in the de novo formation of peroxisomes, thus challenging the prevalent model invoking growth and division of pre-existing peroxisomes. Importantly, a novel sorting process has been recently defined at the ER that segregates and assembles specific sets of peroxisomal membrane proteins (PMPs) into distinct pre-peroxisomal vesicular carriers (ppVs) that later undergo heterotypic fusion to form mature peroxisomes. Consequently, the emerging model has redefined the function of many peroxins (most notably Pex3, Pex19, and Pex25) and assigned them novel roles in vesicular budding and subsequent peroxisome assembly. These advances establish a novel intracellular membrane trafficking route between the ER and peroxisomes, but the components remain elusive. This review will provide a historical perspective and focus on recent developments in the emerging role of the ER in peroxisome biogenesis.

Keywords: ER involvement in peroxisome biogenesis; intracellular protein trafficking; organelle biogenesis; peroxisomal ER; peroxisome; vesicle budding.

Figure 1

Overview of peroxisome biogenesis: converging de novo and growth and division models. PMPs are translated in the cytosol on free ribosomes and are incorporated into the ER membrane through specific translocons (Sec61 or Get3) (van der Zand et al., ; Borgese and Fasana, 2011). It is assumed that the PMPs are segregated and sorted (presumably, through an intramolecular signal) into at least two different pre-peroxisomal compartments (pER) in the ER (Fakieh et al., 2013). These PMPs leave the ER through vesicular carriers that bud in a Pex19 dependent manner (upper inset) (Lam et al., ; Agrawal et al., 2011). These vesicles undergo heterotypic fusion to unite the components of the importomer to form import competent peroxisomes (van der Zand et al., 2012), a process that requires the Pex1 and Pex6 proteins (Titorenko et al., 2000). It is expected that Type II PMPs are incorporated at this stage since they are essential for the import of matrix proteins (Koller et al., 1999). Here Pex19 might act as an mPTS receptor that binds and stabilizes the Type II PMPs in the cytosol and incorporates them into the peroxisomal membrane upon docking to the membrane bound Pex3 (Schmidt et al., 2012) (lower inset). Upon subsequent import of matrix proteins, peroxisomes grow in size and undergo division to replenish cells with an adequate number of peroxisomes to meet metabolic requirements of the cells. This pathway could be the most plausible way by which peroxisomes are repopulated in cells lacking peroxisomes (such as pex3Δ/ pex19Δ) when the missing gene is reintroduced (Hoepfner et al., ; van der Zand et al., ; Agrawal et al., 2011). However, in WT cells as well, ER might supply PMPs to replenish and maintain the actively dividing peroxisomes (Motley and Hettema, 2007). An active interaction between the two pathways would enable cells to adapt dynamically to changing environments.