Phosphorylation Regulates the Ubiquitin-independent Degradation of Yeast Pah1 Phosphatidate Phosphatase by the 20S Proteasome

Hsieh, Lu‐Sheng; Su, Wen Min; Han, Gil Soo; Carman, George M.

doi:10.1074/jbc.m115.648659

Cited by 62 publications

(83 citation statements)

References 104 publications

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“…Using purified preparations of proteasome and a nonphosphorylated version of Pah1 purified from E. coli, in vitro experiments showed that Pah1 is degraded by the 20S proteasome in a ubiquitin-independent manner. Whereas phosphorylation by protein kinase CKII did not affect the susceptibility of Pah1 to 20S proteasome-mediated degradation (46), phosphorylation by protein kinase C slightly increased Pah1 instability and phosphorylation by protein kinase A or Pho85-Pho80 kinase attenuated Pah1 degradation (17). Consistent with this observation, in vivo analysis using nonphosphorylatable variants of Pah1 showed that abrogation of protein kinase C phosphorylation prevented the decrease in abundance of a Pah1 variant refractory to Pho85-Pho80 kinase phosphorylation (45).…”

Section: Pa Phosphatase Balances Membrane Expansion With Lipid Storagesupporting

confidence: 69%

“…Consistent with this observation, in vivo analysis using nonphosphorylatable variants of Pah1 showed that abrogation of protein kinase C phosphorylation prevented the decrease in abundance of a Pah1 variant refractory to Pho85-Pho80 kinase phosphorylation (45). Using Pah1 purified from S. cerevisiae, which would be phosphorylated, it was observed that dephosphorylation by Nem1/Spo7 made Pah1 more susceptible to 20S proteasome degradation (17). The accumulated evidence suggests that changes in Pah1 phosphorylation are part of a sensitization mechanism whereby fully active dephosphorylated Pah1 becomes more susceptible to proteasome degradation.…”

Section: Pa Phosphatase Balances Membrane Expansion With Lipid Storagesupporting

confidence: 57%

“…Upon dephosphorylation by the conserved ER-localized protein phosphatase, Nem1/Spo7, Pah1 becomes membrane bound and active, generating diacylglycerol (DAG) for TAG synthesis (14,15). Remarkably, the active form of Pah1 is unstable and rapidly degraded, resulting in a tightly controlled system for regulation of membrane versus storage lipid synthesis (16,17). PA is the key lipid precursor for the synthesis of TAG and PLs taking place at the nuclear envelope (NE)/ER (green).…”

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confidence: 99%

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Lipid synthesis and membrane contact sites: a crossroads for cellular physiology

Fernández-Murray

McMaster

2016

Journal of Lipid Research

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high throughput analyses, makes this yeast a powerful organism to unveil the intricacies of this field. The yeast S. cerevisiae has played a foundational role in the field of molecular and cellular biology of lipids, including the identification of membrane contact sites (MCSs) and how they link lipid metabolism with organelle dynamics. We present advances in two topics where extensive and outstanding contributions have recently been made where their relevance transcends the yeast lipid field. We first review new information about the phosphatidic acid (PA) phosphatase, Pah1, the yeast homolog of human lipin, and its role in directing lipid flux into membrane synthesis or storage. We review the contribution of Pah1 to lipid droplet (LD) formation and its interaction with the seipin complex, Fld1/Ldb16, to regulate endoplasmic reticulum (ER)-LD contact site dynamics. Second, we recapitulate recent developments revealing MCS connections between the ER and mitochondria with other cellular compartments, and how these intersect with the maintenance of lipid homeostasis. Furthermore, we explore MCS redundancies that allow cells to cope with changing metabolic demand. PA METABOLISM CO-COORDINATES MEMBRANE AND LD SYNTHESISPA is the common precursor for the synthesis of membrane phospholipids (PLs) and the major component of The pervasive importance of lipids in cell biology has become evident. From structural roles defining cellular compartments and surfaces with specific biological properties to functional roles in signal transduction processes and modulation of regulatory networks, the involvement of lipids in varied cellular functions is well-established. Concurrently, we have gained a broad understanding about the repertoire of proteins involved in synthesis, degradation, transport, and sensing of lipids, as well as the regulatory mechanisms that interconnect lipid metabolism with other cellular processes. The amenability of Saccharomyces cerevisiae to classical approaches of molecular genetics, and toThe work on the science described in this review was supported by a Discovery Grant from the Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada to C.R.M. Manuscript received 19 July 2016 and in revised form 6 August 2016. Published, JLR Papers in Press, August 12, 2016 DOI 10.1194 Lipid synthesis and membrane contact sites: a crossroads for cellular physiology Abbreviations: cER, cortical endoplasmic reticulum; ChiMERA, construct helping in mitochondria-endoplasmic reticulum association; CL, cardiolipin; DAG, diacylglycerol; EMC, endoplasmic reticulum membrane protein complex; ER, endoplasmic reticulum; ERMES, endoplasmic reticulum-mitochondria encounter structure; HOPS, homotypic fusion and vacuole protein sorting; Lam, lipid transfer protein anchored at a membrane contact site; LD, lipid droplet; Ltc, lipid transfer at contact site; LTP, lipid transfer protein; Mcp, maintenance of mitochondrial morphology 10 complementing protein; M...

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Section: Pa Phosphatase Balances Membrane Expansion With Lipid Storagesupporting

confidence: 69%

Section: Pa Phosphatase Balances Membrane Expansion With Lipid Storagesupporting

confidence: 57%

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confidence: 99%

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Lipid synthesis and membrane contact sites: a crossroads for cellular physiology

Fernández-Murray

McMaster

2016

Journal of Lipid Research

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“…The phosphorylation of Pah1 by Pkc1 does not affect its location or PA phosphatase activity, but instead affects its stability (3). The Pkc1 phosphorylation of Pah1, which is favored when the enzyme is not phosphorylated on the target sites of Pho85 and Cdc28, promotes its degradation by the 20S proteasome (3,59). Here we showed that the abundance of Pah1 is stabilized in cho1 mutant cells lacking the ability to synthesize PS, which indirectly supports the notion that PS regulates Pkc1 activity in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, the phosphorylation of Pah1 by rat brain PKC stimulates its degradation by the 20S proteasome (59). The phosphorylation-mediated degradation 32 P-labeled Nem1-TM and Spo7-TM in the polyacrylamide gel were transferred to a polyvinylidene difluoride membrane and then treated with HCl or L-1-tosylamido-2-phenylethyl chloromethyl ketone-treated trypsin.…”

Section: Pah1 Abundance Is Stabilized In Yeast Cells Lacking Psmentioning

confidence: 99%

Phosphorylation of lipid metabolic enzymes by yeast protein kinase C requires phosphatidylserine and diacylglycerol

Dey

Han

et al. 2017

Journal of Lipid Research

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The Yarrowia lipolytica PAH1 homologue contributes but is not required for triacylglycerol biosynthesis during growth on glucose

Ukey

Carmon

Hardman

et al. 2020

Yeast

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The PAH1-encoded phosphatidate phosphatase (PAP) catalyzes the Mg 2+ -dependent dephosphorylation of phosphatidate to produce diacylglycerol, which can be acylated to form triacylglycerol (TAG). In the model oleaginous yeast Yarrowia lipolytica, TAG is the major lipid produced, and its biosynthesis requires a continuous supply of diacylglycerol, which can be provided by the PAP reaction. However, the regulation of Pah1 has not been studied in detail in Y. lipolytica, and thus its contribution to the biosynthesis of TAG in this yeast is not well understood. In this work, we examined

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Phosphorylation Regulates the Ubiquitin-independent Degradation of Yeast Pah1 Phosphatidate Phosphatase by the 20S Proteasome

Cited by 62 publications

References 104 publications

Lipid synthesis and membrane contact sites: a crossroads for cellular physiology

Lipid synthesis and membrane contact sites: a crossroads for cellular physiology

Phosphorylation of lipid metabolic enzymes by yeast protein kinase C requires phosphatidylserine and diacylglycerol

The Yarrowia lipolytica PAH1 homologue contributes but is not required for triacylglycerol biosynthesis during growth on glucose

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