The ides of MARCH5: The E3 ligase essential for peroxisome degradation by pexophagy.

A recent study by Zheng et al. (2021. J.

Autophagy Stimulus-Dependent Role of the Small GTPase Ras2 in Peroxisome Degradation.

The changing accessibility of nutrient resources induces the reprogramming of cellular metabolism in order to adapt the cell to the altered growth conditions. The nutrient-depending signaling depends on the kinases mTOR (mechanistic target of rapamycin), which is mainly activated by nitrogen-resources, and PKA (protein kinase A), which is mainly activated by glucose, as well as both of their associated factors. These systems promote protein synthesis and cell proliferation, while they inhibit degradation of cellular content by unselective bulk autophagy.

The Peroxisomal PTS1-Import Defect of - Deficient Cells Is Independent of Pexophagy in .

The important physiologic role of peroxisomes is shown by the occurrence of peroxisomal biogenesis disorders (PBDs) in humans. This spectrum of autosomal recessive metabolic disorders is characterized by defective peroxisome assembly and impaired peroxisomal functions. PBDs are caused by mutations in the peroxisomal biogenesis factors, which are required for the correct compartmentalization of peroxisomal matrix enzymes.

The novel peroxin Pex37: the Pxmp2 family joins the peroxisomal fission machinery.

Peroxisomes can undergo fission during cell division, followed by their segregation between mother and daughter cells. Despite species-specific variations in the molecular composition of the fission machinery, the central mechanistic factors can be assigned to two groups: the Pex11 family and the dynamin-related protein family. In a recent study, Singh et al.

Vps10-mediated targeting of Pep4 determines the activity of the vacuole in a substrate-dependent manner.

The vacuole is the hydrolytic compartment of yeast cells and has a similar function as the lysosome of higher eukaryotes in detoxification and recycling of macromolecules. We analysed the contribution of single vacuolar enzymes to pexophagy and identified the phospholipase Atg15, the V-ATPase factor Vma2 and the serine-protease Prb1 along with the already known aspartyl-protease Pep4 (Proteinase A) to be required for this pathway. We also analysed the trafficking receptor Vps10, which is required for an efficient vacuolar targeting of the precursor form of Pep4.

Vac8 Controls Vacuolar Membrane Dynamics during Different Autophagy Pathways in .

The yeast vacuole is a vital organelle, which is required for the degradation of aberrant intracellular or extracellular substrates and the recycling of the resulting nutrients as newly available building blocks for the cellular metabolism. Like the plant vacuole or the mammalian lysosome, the yeast vacuole is the destination of biosynthetic trafficking pathways that transport the vacuolar enzymes required for its functions. Moreover, substrates destined for degradation, like extracellular endocytosed cargoes that are transported by endosomes/multivesicular bodies as well as intracellular substrates that are transported via different forms of autophagosomes, have the vacuole as destination.

mTOR: A Cellular Regulator Interface in Health and Disease.

The mechanistic target of Rapamycin (mTOR) is a ubiquitously-conserved serine/threonine kinase, which has a central function in integrating growth signals and orchestrating their physiologic effects on cellular level. mTOR is the core component of differently composed signaling complexes that differ in protein composition and molecular targets. Newly identified classes of mTOR inhibitors are being developed to block autoimmune diseases and transplant rejections but also to treat obesity, diabetes, and different types of cancer.

The deubiquitination of the PTS1-import receptor Pex5p is required for peroxisomal matrix protein import.

Peroxisomal biogenesis depends on the correct import of matrix proteins into the lumen of the organelle. Most peroxisomal matrix proteins harbor the peroxisomal targeting-type 1 (PTS1), which is recognized by the soluble PTS1-receptor Pex5p in the cytosol. Pex5p ferries the PTS1-proteins to the peroxisomal membrane and releases them into the lumen.

Regulation of the Tumor-Suppressor BECLIN 1 by Distinct Ubiquitination Cascades.

Autophagy contributes to cellular homeostasis through the degradation of various intracellular targets such as proteins, organelles and microbes. This relates autophagy to various diseases such as infections, neurodegenerative diseases and cancer. A central component of the autophagy machinery is the class III phosphatidylinositol 3-kinase (PI3K-III) complex, which generates the signaling lipid phosphatidylinositol 3-phosphate (PtdIns3P).

ATP-driven processes of peroxisomal matrix protein import.

In peroxisomal matrix protein import two processes directly depend on the binding and hydrolysis of ATP, both taking place at the late steps of the peroxisomal import cycle. First, ATP hydrolysis is required to initiate a ubiquitin-transfer cascade to modify the import (co-)receptors. These receptors display a dual localization in the cytosol and at the peroxisomal membrane, whereas only the membrane bound fraction receives the ubiquitin modification.

The class III phosphatidylinositol 3-kinase Vps34 in Saccharomyces cerevisiae.

The class III phosphatidylinositol 3-kinase Vps34 (vacuolar protein sorting 34) catalyzes for the formation of the signaling lipid phosphatidylinositol-3-phopsphate, which is a central factor in the regulation of autophagy, endocytic trafficking and vesicular transport. In this article, we discuss the functional role of the lipid kinase Vps34 in Saccharomyces cerevisiae.

Regulation of peroxisome dynamics by phosphorylation.

Peroxisomes are highly dynamic organelles that can rapidly change in size, abundance, and protein content in response to alterations in nutritional and other environmental conditions. These dynamic changes in peroxisome features, referred to as peroxisome dynamics, rely on the coordinated action of several processes of peroxisome biogenesis. Revealing the regulatory mechanisms of peroxisome dynamics is an emerging theme in cell biology.

Autophagy-Related Deubiquitinating Enzymes Involved in Health and Disease.

Autophagy is an evolutionarily-conserved process that delivers diverse cytoplasmic components to the lysosomal compartment for either recycling or degradation. This involves the removal of protein aggregates, the turnover of organelles, as well as the elimination of intracellular pathogens. In this situation, when only specific cargoes should be targeted to the lysosome, the potential targets can be selectively marked by the attachment of ubiquitin in order to be recognized by autophagy-receptors.

Regulation of peroxisomal matrix protein import by ubiquitination.

Peroxisomes are organelles that play an important role in many cellular tasks. The functionality of peroxisomes depends on the proper import of their matrix proteins. Peroxisomal matrix proteins are imported posttranslationally in a folded, sometimes even oligomeric state.

Structural insights into cargo recognition by the yeast PTS1 receptor.

The peroxisomal matrix protein import is facilitated by cycling import receptors that shuttle between the cytosol and the peroxisomal membrane. The import receptor Pex5p mediates the import of proteins harboring a peroxisomal targeting signal of type I (PTS1). Purified recombinant Pex5p forms a dimeric complex with the PTS1-protein Pcs60p in vitro with a KD of 0.

Cysteine-specific ubiquitination protects the peroxisomal import receptor Pex5p against proteasomal degradation.

Peroxisomal matrix protein import is mediated by dynamic import receptors, which cycle between the peroxisomal membrane and the cytosol. Proteins with a type 1 peroxisomal targeting signal (PTS1) are bound by the import receptor Pex5p in the cytosol and guided to the peroxisomal membrane. After cargo translocation into the peroxisomal matrix, the receptor is released from the membrane back to the cytosol in an ATP-dependent manner by the AAA-type ATPases Pex1p and Pex6p.

Regulation of the Tumor-Suppressor Function of the Class III Phosphatidylinositol 3-Kinase Complex by Ubiquitin and SUMO.

The occurrence of cancer is often associated with a dysfunction in one of the three central membrane-involution processes-autophagy, endocytosis or cytokinesis. Interestingly, all three pathways are controlled by the same central signaling module: the class III phosphatidylinositol 3-kinase (PI3K-III) complex and its catalytic product, the phosphorylated lipid phosphatidylinositol 3-phosphate (PtdIns3P). The activity of the catalytic subunit of the PI3K-III complex, the lipid-kinase VPS34, requires the presence of the membrane-targeting factor VPS15 as well as the adaptor protein Beclin 1.

The cytosolic domain of Pex22p stimulates the Pex4p-dependent ubiquitination of the PTS1-receptor.

Peroxisomal biogenesis is an ubiquitin-dependent process because the receptors required for the import of peroxisomal matrix proteins are controlled via their ubiquitination status. A key step is the monoubiquitination of the import receptor Pex5p by the ubiquitin-conjugating enzyme (E2) Pex4p. This monoubiquitination is supposed to take place after Pex5p has released the cargo into the peroxisomal matrix and primes Pex5p for the extraction from the membrane by the mechano-enzymes Pex1p/Pex6p.

The peroxisomal receptor dislocation pathway: to the exportomer and beyond.

The biogenesis of peroxisomes is an ubiquitin-dependent process. In particular, the import of matrix proteins into the peroxisomal lumen requires the modification of import receptors with ubiquitin. The matrix proteins are synthesized on free polyribosomes in the cytosol and are recognized by import receptors via a peroxisomal targeting sequence (PTS).

Import of proteins into the peroxisomal matrix.

Peroxisomes constitute a dynamic compartment in all nucleated cells. They fulfill diverse metabolic tasks in response to environmental changes and cellular demands. This adaptation is implemented by modulation of the enzyme content of the organelles, which is accomplished by dynamically operating peroxisomal protein transport machineries.