Hph1 and Hph2 Are Novel Components of the Sec63/Sec62 Posttranslational Translocation Complex That Aid in Vacuolar Proton ATPase Biogenesis

Piña, Francisco; O’Donnell, Allyson F.; Pagant, Silvère; Piao, Hai Lan; Miller, John P.; Fields, Stanley; Miller, Elizabeth A.; Cyert, Martha S.

doi:10.1128/ec.00241-10

Cited by 15 publications

(11 citation statements)

References 50 publications

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“…Calcineurin-mediated dephosphorylation positively modulates Hph1. More recently it has been described [285] that Hph1 (and Hph2) act with the Sec63/Sec62 complex and that defects in this complex results in destabilization of Vph1, a subunit of the vacuolar proton ATPase (V-ATPase).…”

Section: Pp2b (Pp3 Calcineurin) and Pp2b-related Enzymesmentioning

confidence: 99%

Ser/Thr protein phosphatases in fungi: structure, regulation and function

2019

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Reversible phospho-dephosphorylation of proteins is a major mechanism for the control of cellular functions. By large, Ser and Thr are the most frequently residues phosphorylated in eukar-yotes. Removal of phosphate from these amino acids is catalyzed by a large family of well-conserved enzymes, collectively called Ser/Thr protein phosphatases. The activity of these enzymes has an enormous impact on cellular functioning. In this work we pre-sent the members of this family in S. cerevisiae and other fungal species, and review the most recent findings concerning their regu-lation and the roles they play in the most diverse aspects of cell biology.

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Section: Pp2b (Pp3 Calcineurin) and Pp2b-related Enzymesmentioning

confidence: 99%

Ser/Thr protein phosphatases in fungi: structure, regulation and function

2019

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“…Calcineurin dephosphorylates a range of protein targets in yeast, including the Crz1 transcription factor, which rapidly translocates from the cytosol to the nucleus upon dephosphorylation to express genes encoding cell wall biosynthetic enzymes (Fks2), ion pumps (Pmc1, Pmr1, and Ena1), signaling enzymes (Cmk2), components of vesicle trafficking (Gyp7 and Ypt53), and regulators of calcineurin (Rcn1) (Yoshimoto et al 2002;Cyert 2003;Heath et al 2004;Viladevall et al 2004;Bultynck et al 2006). In addition to Crz1, calcineurin dephosphorylates proteins involved in ER translocation (Hph1) (Pina et al 2011), TORC2 effectors (Slm1 and Slm2) (Bultynck et al 2006;Berchtold et al 2012;Niles et al 2012), its regulator (Rcn1) (Hilioti et al 2004), and as mentioned, may regulate K + transporters (Mendoza et al 1994) (Figure 3). In response to excess amino acids, calcineurin also activates endocytosis of the Dip5 amino acid transporter by dephosphorylating the a-arrestin trafficking adaptor, Aly1/ Art6 (A. F. O'Donnell, unpublished results).…”

Section: Ca 2+ -Dependent Signaling Pathwaysmentioning

confidence: 99%

Regulation of Cation Balance inSaccharomyces cerevisiae

2013

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All living organisms require nutrient minerals for growth and have developed mechanisms to acquire, utilize, and store nutrient minerals effectively. In the aqueous cellular environment, these elements exist as charged ions that, together with protons and hydroxide ions, facilitate biochemical reactions and establish the electrochemical gradients across membranes that drive cellular processes such as transport and ATP synthesis. Metal ions serve as essential enzyme cofactors and perform both structural and signaling roles within cells. However, because these ions can also be toxic, cells have developed sophisticated homeostatic mechanisms to regulate their levels and avoid toxicity. Studies in Saccharomyces cerevisiae have characterized many of the gene products and processes responsible for acquiring, utilizing, storing, and regulating levels of these ions. Findings in this model organism have often allowed the corresponding machinery in humans to be identified and have provided insights into diseases that result from defects in ion homeostasis. This review summarizes our current understanding of how cation balance is achieved and modulated in baker's yeast. Control of intracellular pH is discussed, as well as uptake, storage, and efflux mechanisms for the alkali metal cations, Na + and K + , the divalent cations, Ca 2+ and Mg 2+ , and the trace metal ions, Fe 2+ , Zn 2+ , Cu 2+ , and Mn 2+ . Signal transduction pathways that are regulated by pH and Ca 2+ are reviewed, as well as the mechanisms that allow cells to maintain appropriate intracellular cation concentrations when challenged by extreme conditions, i.e., either limited availability or toxic levels in the environment. TABLE OF CONTENTS Abstract 677Introduction 678

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“…Remarkably, the processes regulated by all of these proteins are disturbed by α-syn in yeast and in neurons. Hph1p facilitates the posttranslational translocation of proteins, especially those involved in vacuolar ion homeostasis and vesicular trafficking (35). Slm2p acts via the target of rapamycin complex 2 (TORC2) to support cytoskeletal organization and lipid homeostasis (20,(36)(37)(38).…”

Section: Calcineurin Activation By Calmodulin Has Both Protective Andmentioning

confidence: 99%

Calcineurin determines toxic versus beneficial responses to α-synuclein

Caraveo

Auluck

Whitesell

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

105

144

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Calcineurin (CN) is a highly conserved Ca 2+ -calmodulin (CaM)-dependent phosphatase that senses Ca 2+ concentrations and transduces that information into cellular responses. Ca 2+ homeostasis is disrupted by α-synuclein (α-syn), a small lipid binding protein whose misfolding and accumulation is a pathological hallmark of several neurodegenerative diseases. We report that α-syn, from yeast to neurons, leads to sustained highly elevated levels of cytoplasmic Ca 2+ , thereby activating a CaM-CN cascade that engages substrates that result in toxicity. Surprisingly, complete inhibition of CN also results in toxicity. Limiting the availability of CaM shifts CN's spectrum of substrates toward protective pathways. Modulating CN or CN's substrates with highly selective genetic and pharmacological tools (FK506) does the same. FK506 crosses the blood brain barrier, is well tolerated in humans, and is active in neurons and glia. Thus, a tunable response to CN, which has been conserved for a billion years, can be targeted to rebalance the phosphatase's activities from toxic toward beneficial substrates. These findings have immediate therapeutic implications for synucleinopathies.

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Hph1 and Hph2 Are Novel Components of the Sec63/Sec62 Posttranslational Translocation Complex That Aid in Vacuolar Proton ATPase Biogenesis

Abstract: Hph1 and Hph2 are homologous integral endoplasmic reticulum (ER) membrane proteins required for

Cited by 15 publications

References 50 publications

Ser/Thr protein phosphatases in fungi: structure, regulation and function

Ser/Thr protein phosphatases in fungi: structure, regulation and function

Regulation of Cation Balance inSaccharomyces cerevisiae

Calcineurin determines toxic versus beneficial responses to α-synuclein

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