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Like primary mouse islets, MIN6 pseudoislets responded to the depolarization by 40 mm KCl and the resulting increase in the free cytosolic Ca2+ concentration ([Ca2+]i) with a massive increase in insulin secretion, whereas 15 mm KCl had little effect in spite of a clear increase in [Ca2+]i. Analysis of insulin‐enhanced green fluorescent protein (EGFP)‐labeled granules in MIN6 cells by total internal...
Previous work has showed that ergosterol and sphingolipids become sorted to secretory vesicles immunoisolated using a chimeric, artificial raft membrane protein as bait. In this study, we have extended this analysis to three populations of secretory vesicles isolated using natural yeast plasma membrane (PM) proteins: Pma1p, Mid2p and Gap1*p as baits. We compared the lipidomes of the immunoisolated...
Ligand‐mediated lysosomal degradation of growth factor receptors, mediated by the endosomal sorting complex required for transport (ESCRT) machinery, is a mechanism that attenuates the cellular response to growth factors. In this article, we present a novel regulatory mechanism that involves ligand‐mediated degradation of a key component of the sorting machinery itself. We have investigated the endosomal localization of subunits of the four ESCRTs—Hrs (ESCRT‐0), Tsg101 (ESCRT‐I), EAP30/Vps22 (ESCRT‐II) and charged multivesicular body protein 3/Vps24 (ESCRT‐III). All the components were detected on the limiting membrane of multivesicular endosomes (MVEs). Surprisingly, however, Tsg101 and other ESCRT‐I subunits were also detected within intraluminal vesicles (ILVs) of MVEs. Tsg101 was sequestered along with cargo during endosomal sorting into ILVs and further degraded in lysosomes. Importantly, ESCRT‐mediated downregulation of two distinct cargoes, epidermal growth factor receptor (EGFR) and connexin43, mutually made cells refractory to degradation of the other cargo. Our observations indicate that the degradation of a key ESCRT component along with cargo represents a novel feedback control of endosomal sorting by preventing collateral degradation of cell surface receptors following stimulation of one specific pathway.
The viral factories of mammalian reovirus (MRV) are cytoplasmic structures that serve as sites of viral genome replication and particle assembly. A 721‐aa MRV non‐structural protein, µNS, forms the factory matrix and recruits other viral proteins to these structures. In this report, we show that µNS contains a conserved C‐proximal sequence (711‐LIDFS‐715) that is similar to known clathrin‐box motifs and is required for recruitment of clathrin to viral factories. Clathrin recruitment by µNS occurs independently of infecting MRV particles or other MRV proteins. Ala substitution for a single Leu residue (mutation L711A) within the putative clathrin‐binding motif of µNS inhibits clathrin recruitment, but does not prevent formation or expansion of viral factories. Notably, clathrin‐dependent cellular functions, including both endocytosis and secretion, are disrupted in cells infected with MRV expressing wild‐type, but not L711A, µNS. These results identify µNS as a novel adaptor‐like protein that recruits cellular clathrin to viral factories, disrupting normal functions of clathrin in cellular membrane trafficking. To our knowledge, this is the only viral or bacterial protein yet shown to interfere with clathrin functions in this manner. The results additionally establish a new approach for studies of clathrin functions, based on µNS‐mediated sequestration.
Trafficking of soluble proteins to the apicoplast in Plasmodium falciparum is determined by an N‐terminal transit peptide (TP) which is necessary and sufficient for apicoplast import. Apicoplast precursor proteins are synthesized at the rough endoplasmic reticulum, but are then specifically sorted from other proteins in the secretory pathway. The mechanism of TP recognition is presently unknown. Apicoplast...
Interstitial lung disease in both children and adults has been linked to mutations in the lung‐specific surfactant protein C (SFTPC) gene. Among these, the missense mutation [isoleucine to threonine at codon 73 = human surfactant protein C (hSP‐CI73T)] accounts for ∼30% of all described SFTPC mutations. We reported previously that unlike the BRICHOS misfolding SFTPC mutants, expression of hSP‐CI73T...
Eukaryotic tail‐anchored (TA) membrane proteins are inserted into the endoplasmic reticulum by a post‐translational TRC40 pathway, but no comparable pathway is known in other domains of life. The crystal structure of an archaebacterial TRC40 sequence homolog bound to ADP•AlF4− reveals characteristic features of eukaryotic TRC40, including a zinc‐mediated dimer and a large hydrophobic groove. Moreover, archaeal TRC40 interacts with the transmembrane domain of TA substrates and directs their membrane insertion. Thus, the TRC40 pathway is more broadly conserved than previously recognized.
Regulated intramembrane proteolysis is an evolutionarily conserved mechanism by which membrane‐anchored bioactive molecules are released from cellular membranes. In eukaryotic cells, intramembrane proteases are found in different cellular organelles ranging from the endosomal system to mitochondria and chloroplasts. These proteases function in diverse processes such as transcription control, regulated growth factor secretion and recently even a role in the control of mitophagy has been suggested. Genomic annotation has predicted 13 different intramembrane proteases in humans. Apart from few studied examples, very little is known about their function. This review describes emerging principles of how intramembrane proteases contribute to the regulation of cellular protein trafficking in eukaryotic cells and raises the important question of how their activity is controlled....
Cargo proteins of the biosynthetic secretory pathway are folded in the endoplasmic reticulum (ER) and proceed to the trans Golgi network for sorting and targeting to the apical or basolateral sides of the membrane, where they exert their function. These processes depend on diverse protein domains. Here, we used CD39 (NTPdase1), a modulator of thrombosis and inflammation, which contains an extracellular and two transmembrane domains (TMDs), as a model protein to address comprehensively the role of native TMDs in folding, polarized transport and biological activity. In MDCK cells, CD39 exits Golgi dynamin‐dependently and is targeted to the apical side of the membrane. Although the N‐terminal TMD possesses an apical targeting signal, the N‐ and C‐terminal TMDs are not required for apical targeting of CD39. Folding and transport to the plasma membrane relies only on the C‐terminal TMD, while the N‐terminal one is redundant. Nevertheless, both N‐ and C‐terminal anchoring as well as genuine TMDs are critical for optimal enzymatic activity and activation by cholesterol. We conclude therefore that TMDs are not just mechanical linkers between proteins and membranes but are also able to control folding and sorting, as well as biological activity via sensing components of lipid bilayers.
APPL endosomes are a recently identified subpopulation of early endosomes characterized by the presence of two homologous Rab5 effector proteins APPL1 and APPL2. They exhibit only limited colocalization with EEA1, another Rab5 effector and a marker of the canonical early endosomes. Although APPL endosomes appear to play important roles in cargo trafficking and signal transduction, their protein composition...
Syntaxins and interacting SNARE proteins enable membrane fusion in diverse trafficking pathways. The Arabidopsis SYP1 family of plasma membrane‐localized syntaxins comprises nine members, of which KNOLLE and PEN1 play specific roles in cytokinesis and innate immunity, respectively. To identify mechanisms conferring specificity of action, we examined one member of each subfamily—KNOLLE/SYP111, PEN1/SYP121...
ATP‐binding cassette (ABC) transporters are well known for their roles as multidrug resistance determinants but also play important roles in regulation of lipid levels. In the yeast Saccharomyces cerevisiae, the plasma membrane ABC transporter proteins Pdr5 and Yor1 are required for normal rates of transport of phosphatidyethanolamine to the surface of the cell. Loss of these ABC transporters causes...
The ATP‐sensitive potassium (KATP) channel consisting of sulfonylurea receptor 1 (SUR1) and inward‐rectifier potassium channel 6.2 (Kir6.2) has a well‐established role in insulin secretion. Mutations in either subunit can lead to disease due to aberrant channel gating, altered channel density at the cell surface or a combination of both. Endocytic trafficking of channels at the plasma membrane is...
In neurons, many receptors must be localized correctly to axons or dendrites for proper function. During development, receptors for nerve growth and guidance are targeted to axons and localized to growth cones where receptor activation by ligands results in promotion or inhibition of axon growth. Signaling outcomes downstream of ligand binding are determined by the location, levels and residence times...
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