Post-transcriptional Regulation of the Yeast High Affinity Iron Transport System

Felice, Maria Rosa; Domenico, Ivana De; Li, Liangtao; Ward, Diane McVey; Bartók, Beatrix; Musci, Giovanni; Kaplan, Jerry

doi:10.1074/jbc.m414663200

Cited by 95 publications

(110 citation statements)

References 38 publications

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“…Snx3 functions as a cargo-specific adapter in this pathway, binding both to a recycling signal in Ftr1 and to the retromer complex. In contrast, when cells are exposed to a high concentration of extracellular iron, the transporter is diverted to the lysosome-like vacuole for degradation (Felice et al, 2005). The mechanism governing the switch between endocytic recycling and iron-induced degradation is unknown.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Thus, we sought to address the possible role of Fet3-Ftr1 ubiquitylation with respect to the recycling versus degradation sorting decision by generating cis-acting mutations within the cargo itself. The Ftr1 subunit of the iron transporter is reported to be ubiquitylated in response to iron shock (Felice et al, 2005), so we mutated every lysine residue to arginine within the cytosolic segments of Fet3 (Fet3-K/R), Ftr1 (Ftr1-K/R), or both Fet3 and Ftr1, hereafter referred to as Fet3-Ftr1 22 K/R ( Figure 4A and Supplementary Figure S1A). The mutant genes were integrated at their native chromosomal loci to ensure expression from their native promoters, and so that they are the sole copies of FET3 and FTR1 in the cell.…”

Section: Constitutive Endocytic Recycling Of Fet3-ftr1 Lacking Cytosomentioning

confidence: 99%

“…When cells are starved for iron, Fet3-Ftr1 is unusually stable because it is maintained at the plasma membrane due to retromer-dependent endocytic recycling (Strochlic et al, 2007). However, when cells are exposed to a high concentration of free iron in the culture medium, endocytosed Fet3-Ftr1 is transported to the vacuole and degraded (Felice et al, 2005).In a prior study, we showed that the sorting nexin, Snx3, directly recognizes a cytosolic signal in Ftr1 that is required for retromer-mediated retrograde transport (Strochlic et al, 2007). Snx3 and retromer physically associate, and they cooperate to prevent vacuolar degradation of Fet3-Ftr1 when cells are starved for iron.…”

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Opposing Activities of the Snx3-Retromer Complex and ESCRT Proteins Mediate Regulated Cargo Sorting at a Common Endosome

Strochlic

Schmiedekamp

Lee

et al. 2008

MBoC

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Endocytosed proteins are either delivered to the lysosome to be degraded or are exported from the endosomal system and delivered to other organelles. Sorting of the Saccharomyces cerevisiae reductive iron transporter, composed of the Fet3 and Ftr1 proteins, in the endosomal system is regulated by available iron; in iron-starved cells, Fet3-Ftr1 is sorted by Snx3/Grd19 and retromer into a recycling pathway that delivers it back to the plasma membrane, but when starved cells are exposed to iron, Fet3-Ftr1 is targeted to the lysosome-like vacuole and is degraded. We report that iron-induced endocytosis of Fet3-Ftr1 is independent of Fet3-Ftr1 ubiquitylation, and after endocytosis, degradation of Fet3-Ftr1 is mediated by the multivesicular body (MVB) sorting pathway. In mutant cells lacking any component of the ESCRT protein-dependent MVB sorting machinery, the Rsp5 ubiquitin ligase, or in wild-type cells expressing Fet3-Ftr1 lacking cytosolic lysyl ubiquitin acceptor sites, Fet3-Ftr1 is constitutively sorted into the recycling pathway independent of iron status. In the presence and absence of iron, Fet3-Ftr1 transits an endosomal compartment where a subunit of the MVB sorting receptor (Vps27), Snx3/Grd19, and retromer proteins colocalize. We propose that this endosome is where Rsp5 ubiquitylates Fet3-Ftr1 and where the recycling and degradative pathways diverge. INTRODUCTIONThe endocytic pathway is initiated with the internalization of protein and lipid cargo from the plasma membrane. After endocytosis, internalized molecules transit through the endosomal system, a network of interconnected organelles that process and sort cargo molecules back to the plasma membrane, to other organelles, or to lysosomes for degradation. In mammalian cells, early endosomes are pleiomorphic organelles composed of vacuolar domains that contain lumenal vesicles and tubular domains that lead into and emanate from the vacuolar portion. This distinct architecture has functional significance. The tubular elements of the organelle are regions where the majority of internalized plasma membrane proteins and lipids are exported and recycled from the endosomal system via bulk flow and cargo-specific processes (Mayor et al., 1993;Maxfield and McGraw, 2004;Bonifacino and Rojas, 2006). Cargo proteins that are not exported are delivered to lysosomes and many of these are degraded. This occurs via an active, signal-mediated event in which these proteins are targeted to the vacuolar region of the endosome where they are incorporated into vesicles that bud from the limiting membrane into the lumen of the organelle (Piper and Katzmann, 2007). During endosome maturation lumenal vesicles accrue until fusion of the late endosome with the lysosome results in degradation of these vesicles and their contents. A central sorting function of the endosomal system is thus to segregate cargo to be exported from the endosome from cargo to be degraded via lysosomal proteolysis.The core components of the recycling (retrograde) and degradative sorting pathways have be...

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Constitutive Endocytic Recycling Of Fet3-ftr1 Lacking Cytosomentioning

confidence: 99%

mentioning

confidence: 99%

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Opposing Activities of the Snx3-Retromer Complex and ESCRT Proteins Mediate Regulated Cargo Sorting at a Common Endosome

Strochlic

Schmiedekamp

Lee

et al. 2008

MBoC

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“…Almost all studies on iron metabolism have used an iron concentration of 1 mM or lower (Kumanovics et al, 2008;Puig et al, 2008), while the yeast response to 1 mM or higher iron, designated an iron-surplus condition, has not yet been extensively studied. Surplus iron has long been recognized as producing free radicals in the presence of oxygen, and is thus cytotoxic to cells (Felice et al, 2005;Yamaguchi-Iwai et al, 1996). For instance, iron-mediated lipid peroxidation attacks mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Expression Profiling Reveals an Unexpected Growth-Stimulating Effect of Surplus Iron on the Yeast Saccharomyces cerevisiae

Wang

2012

Molecules and Cells

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Iron homeostasis plays a crucial role in growth and division of cells in all kingdoms of life. Although yeast iron metabolism has been extensively studied, little is known about the molecular mechanism of response to surplus iron. In this study, expression profiling of Saccharomyces cerevisiae in the presence of surplus iron revealed a dual effect at 1 and 4 h. A cluster of stress-responsive genes was upregulated via activation of the stress-resistance transcription factor Msn4, which indicated the stress effect of surplus iron on yeast metabolism. Genes involved in aerobic metabolism and several anabolic pathways are also upregulated in iron-surplus conditions, which could significantly accelerate yeast growth. This dual effect suggested that surplus iron might participate in a more complex metabolic network, in addition to serving as a stress inducer. These findings contribute to our understanding of the global response of yeast to the fluctuating availability of iron in the environment.

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From transporter to transceptor: Signaling from transporters provokes re‐evaluation of complex trafficking and regulatory controls

et al. 2011

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When cells are starved of their substrate, many nutrient transporters are induced. These undergo rapid endocytosis and redirection of their intracellular trafficking when their substrate becomes available again. The discovery that some of these transporters also act as receptors, or transceptors, suggests that at least part of the sophisticated controls governing the trafficking of these proteins has to do with their signaling function rather than with control of transport. In yeast, the general amino acid permease Gap1 mediates signaling to the protein kinase A pathway. Its endocytic internalization and intracellular trafficking are subject to amino acid control. Other nutrient transceptors controlling this signal transduction pathway appear to be subject to similar trafficking regulation. Transporters with complex regulatory control have also been suggested to function as transceptors in other organisms. Hence, precise regulation of intracellular trafficking in nutrient transporters may be related to the need for tight control of nutrient-induced signaling.

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Post-transcriptional Regulation of the Yeast High Affinity Iron Transport System

Cited by 95 publications

References 38 publications

Opposing Activities of the Snx3-Retromer Complex and ESCRT Proteins Mediate Regulated Cargo Sorting at a Common Endosome

Opposing Activities of the Snx3-Retromer Complex and ESCRT Proteins Mediate Regulated Cargo Sorting at a Common Endosome

Expression Profiling Reveals an Unexpected Growth-Stimulating Effect of Surplus Iron on the Yeast Saccharomyces cerevisiae

From transporter to transceptor: Signaling from transporters provokes re‐evaluation of complex trafficking and regulatory controls

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