Peroxisomes are dynamic organelles that often proliferate in response to compounds that they metabolize. Peroxisomes can proliferate by two apparent mechanisms, division of preexisting peroxisomes and de novo synthesis of peroxisomes. Evidence for de novo peroxisome synthesis comes from studies of cells lacking the peroxisomal integral membrane peroxin Pex3p. These cells lack peroxisomes, but peroxisomes can assemble upon reintroduction of Pex3p. The source of these peroxisomes has been the subject of debate. Here, we show that the amino-terminal 46 amino acids of Pex3p of Saccharomyces cerevisiae target to a subdomain of the endoplasmic reticulum and initiate the formation of a preperoxisomal compartment for de novo peroxisome synthesis. In vivo video microscopy showed that this preperoxisomal compartment can import both peroxisomal matrix and membrane proteins leading to the formation of bona fide peroxisomes through the continued activity of full-length Pex3p. Peroxisome formation from the preperoxisomal compartment depends on the activity of the genes PEX14 and PEX19, which are required for the targeting of peroxisomal matrix and membrane proteins, respectively. Our findings support a direct role for the endoplasmic reticulum in de novo peroxisome formation.A characteristic of eukaryotic cells is the presence of seemingly distinct subcellular compartments or organelles possessing specific sets of proteins required for specialized cellular functions. However, organelles do not exist in isolation, and interorganellar communication through the movement and exchange of different molecules is required for normal cell function. This interdependence of organelles extends beyond their biochemical and metabolic roles and necessitates that their biogenesis and turnover also be coordinated.The peroxisome has long been considered an autonomous organelle that proliferates by the growth and division of preexisting peroxisomes (1) and is inherited as a functional organelle at cell division. But what of the concept of de novo peroxisome biogenesis? From an evolutionary point of view, peroxisome proliferation and inheritance could have evolved as a response to a slow and perhaps unreliable mechanism of de novo peroxisome biogenesis. However, de novo peroxisome biogenesis, when combined with peroxisome growth, division, and inheritance, would provide the cell with a fail-safe system for peroxisome maintenance and ultimately for its survival.Evidence implicating the endoplasmic reticulum (ER) 3 in peroxisome biogenesis has accumulated in recent years (reviewed in Refs. 2-4). The amino-terminal 16 amino acids of the peroxisomal integral membrane protein Pex3p of Hansenula polymorpha were shown to be sufficient to target a reporter protein to the ER (5), whereas treatment of cells of this yeast with brefeldin A led to the accumulation of newly synthesized peroxisomal membrane and matrix proteins at the ER (6). In the yeast Yarrowia lipolytica, the peroxisomal membrane proteins Pex2p and Pex16p were shown to traffic through the E...

The faithful inheritance of organelles by daughter cells is essential to maintain the benefits afforded to eukaryotic cells by compartmentalization of biochemical functions. In Saccharomyces cerevisiae, the class V myosin, Myo2p, is involved in transporting different organelles, including the peroxisome, along actin cables to the bud. We identified Inp2p as the peroxisome-specific receptor for Myo2p. Cells lacking Inp2p fail to partition peroxisomes to the bud but are unaffected in the inheritance of other organelles. Inp2p is a peroxisomal membrane protein, preferentially enriched in peroxisomes delivered to the bud. Inp2p interacts directly with the globular tail of Myo2p. Cells overproducing Inp2p often transfer their entire populations of peroxisomes to buds. The levels of Inp2p oscillate with the cell cycle. Organelle-specific receptors like Inp2p explain how a single motor can move different organelles in distinct and specific patterns. To our knowledge, Inp2p is the first peroxisomal protein implicated in the vectorial movement of peroxisomes.

Cells have evolved molecular mechanisms for the efficient transmission of organelles during cell division. Little is known about how peroxisomes are inherited. Inp1p is a peripheral membrane protein of peroxisomes of Saccharomyces cerevisiae that affects both the morphology of peroxisomes and their partitioning during cell division. In vivo 4-dimensional video microscopy showed an inability of mother cells to retain a subset of peroxisomes in dividing cells lacking the INP1 gene, whereas cells overexpressing INP1 exhibited immobilized peroxisomes that failed to be partitioned to the bud. Overproduced Inp1p localized to both peroxisomes and the cell cortex, supporting an interaction of Inp1p with specific structures lining the cell periphery. The levels of Inp1p vary with the cell cycle. Inp1p binds Pex25p, Pex30p, and Vps1p, which have been implicated in controlling peroxisome division. Our findings are consistent with Inp1p acting as a factor that retains peroxisomes in cells and controls peroxisome division. Inp1p is the first peroxisomal protein directly implicated in peroxisome inheritance.

Eukaryotic cells divide their metabolic labor between functionally distinct, membrane-enveloped organelles, each precisely tailored for a specific set of biochemical reactions. Peroxisomes are ubiquitous, endoplasmic reticulum-derived organelles that perform requisite biochemical functions intimately connected to lipid metabolism. Upon cell division, cells have to strictly control peroxisome division and inheritance to maintain an appropriate number of peroxisomes in each cell. Peroxisome division follows a specific sequence of events that include peroxisome elongation, membrane constriction, and peroxisome fission. Pex11 proteins mediate the elongation step of peroxisome division, whereas dynamin-related proteins execute the final fission. The mechanisms responsible for peroxisome membrane constriction are poorly understood. Molecular players involved in peroxisome inheritance are just beginning to be elucidated. Inp1p and Inp2p are two recently identified peroxisomal proteins that perform antagonistic functions in regulating peroxisome inheritance in budding yeast. Inp1p promotes the retention of peroxisomes in mother cells and buds by attaching peroxisomes to as-yet-unidentified cortical structures. Inp2p is implicated in the motility of peroxisomes by linking them to the Myo2p motor, which then propels their movement along actin cables. The functions of Inp1p and Inp2p are cell cycle regulated and coordinated to ensure a fair distribution of peroxisomes at cytokinesis.

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Eukaryotic cells have evolved molecular mechanisms to ensure the faithful partitioning of cellular components during cell division. The budding yeast Saccharomyces cerevisiae has to actively deliver about half of its organelles to the growing bud, while retaining the remaining organelles in the mother cell. Until lately, little was known about the inheritance of peroxisomes. Recent studies have identified the peroxisomal proteins Inp1p and Inp2p as two key regulators of peroxisome inheritance that perform antagonistic functions. Inp1p is required for the retention of peroxisomes in mother cells, whereas Inp2p promotes the bud-directed movement of these organelles. Inp1p anchors peroxisomes to the cell cortex by interacting with specific structures lining the cell periphery. On the other hand, Inp2p functions as the peroxisome-specific receptor for the class V myosin, Myo2p, thereby linking peroxisomes to the translocation machinery that propels peroxisome movement. Tight coordination between Inp1p and Inp2p ensures a fair and harmonious spatial segregation of peroxisomes upon cell division.

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