An evolutionarily conserved phosphatidate phosphatase maintains lipid droplet number and ER morphology but not nuclear morphology

Pillai, Anoop Narayana; Shukla, Sushmita; Rahaman, Abdur

doi:10.1242/bio.028233

Cited by 15 publications

(8 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1b), but none complemented the heat stress phenotype. During the course of our study, a minimal lipin/Pah from the ciliate T. thermophila (Tt) (known as Tt Pah2) was reported to also complement the glycerol phenotype, but not the heat stress phenotype of Sc pah1Δ cells 29,30 . We subsequently crystallized Tt Pah2.…”

Section: Resultsmentioning

confidence: 98%

Crystal structure of a lipin/Pah phosphatidic acid phosphatase

et al. 2020

View full text Add to dashboard Cite

Lipin/Pah phosphatidic acid phosphatases (PAPs) generate diacylglycerol to regulate triglyceride synthesis and cellular signaling. Inactivating mutations cause rhabdomyolysis, autoinflammatory disease, and aberrant fat storage. Disease-mutations cluster within the conserved N-Lip and CLip regions that are separated by 500-residues in humans. To understand how the N-Lip and CLip combine for PAP function, we determined crystal structures of Tetrahymena thermophila Pah2 (Tt Pah2) that directly fuses the N-Lip and CLip. Tt Pah2 adopts a two-domain architecture where the N-Lip combines with part of the CLip to form an immunoglobulin-like domain and the remaining CLip forms a HAD-like catalytic domain. An N-Lip CLip fusion of mouse lipin-2 is catalytically active, which suggests mammalian lipins function with the same domain architecture as Tt Pah2. HDX-MS identifies an N-terminal amphipathic helix essential for membrane association. Disease-mutations disrupt catalysis or destabilize the protein fold. This illustrates mechanisms for lipin/Pah PAP function, membrane association, and lipin-related pathologies.

show abstract

Section: Resultsmentioning

confidence: 98%

Crystal structure of a lipin/Pah phosphatidic acid phosphatase

et al. 2020

View full text Add to dashboard Cite

show abstract

“…A linchpin in this regulatory system is provided by lipins, a group of proteins with dual functions in lipid synthesis and the genomic control of energy metabolism. Lipins, which are conserved among all eukaryotes, can convert phosphatidic acid into diacylglycerol as phosphatidate phosphatases (PAP) (3)(4)(5). This activity is required for TAG synthesis and the synthesis of membrane phospholipids (6).…”

Section: Introductionmentioning

confidence: 99%

Nuclear translocation ability of Lipin differentially affects gene expression and survival in fed and fasting Drosophila

Hood

Kofler

Chen

et al. 2020

Journal of Lipid Research

View full text Add to dashboard Cite

Lipins are eukaryotic proteins with functions in lipid synthesis and the homeostatic control of energy balance. They execute these functions by acting as phosphatidate phosphatase enzymes in the cytoplasm and by changing gene expression after translocation into the cell nucleus, in particular under fasting conditions. Here, we asked whether nuclear translocation and enzymatic activity of Drosophila Lipin serve essential functions and how gene expression changes, under both fed and fasting conditions, when nuclear translocation is impaired. To address these questions, we created a Lipin null mutant, a mutant expressing Lipin lacking a nuclear localization signal (LipinΔNLS), and a mutant expressing enzymatically dead Lipin. Our data support the conclusion that the enzymatic, but not the nuclear gene regulatory activity of Lipin, is essential for survival. Notably, adult LipinΔNLS flies were not only viable but also exhibited improved life expectancy. In contrast, they were highly susceptible to starvation. Both the improved life expectancy in the fed state and the decreased survival in the fasting state correlated with changes in metabolic gene expression. Moreover, increased life expectancy of fed flies was associated with a decreased metabolic rate. Interestingly, in addition to metabolic genes, genes involved in feeding behavior and the immune response were mis-regulated in LipinΔNLS flies. Combined, our data suggest that nuclear activity of Lipin influences the genomic response to nutrient availability with effects on life expectancy and starvation resistance. Thus, nutritional or therapeutic approaches that aim at lowering nuclear translocation of lipins in humans may be worth exploring.

show abstract

“…Decreased levels of DAG and TAG were observed in the Mopah1 mutant, which has also been observed in pah1 mutants of S. cerevisiae , F. graminearum , and Yarrowia lipolytica (Karanasios et al, 2010; Oh et al, 2017; Ukey et al, 2020). The reduction of TAG levels leads to a reduced level of lipid droplets in pah1 mutants of Tetrahymena thermophila and F. graminearum (Liu, Yun, et al, 2019a; Liu, Liang, et al,2019b; Pillai et al, 2017; Shi et al, 2018). The KEGG pathway and GO term analyses of the Mopah1 mutant showed that many DEGs are related to lipid and glycolysis/gluconeogenesis metabolism.…”

Section: Discussionmentioning

confidence: 99%

The MoPah1 phosphatidate phosphatase is involved in lipid metabolism, development, and pathogenesis in Magnaporthe oryzae

Zhao

Sun

et al. 2022

Molecular Plant Pathology

View full text Add to dashboard Cite

As with the majority of the hemibiotrophic fungal pathogens, the rice blast fungus Magnaporthe oryzae uses highly specialized infection structures called appressoria for plant penetration. Appressoria differentiated from germ tubes rely on enormous turgor pressure to directly penetrate the plant cell, in which process lipid metabolism plays a critical role. In this study, we characterized the MoPAH1 gene in M. oryzae, encoding a putative highly conserved phosphatidate phosphatase. The expression of MoPAH1 was up-regulated during plant infection. The MoPah1 protein is expressed at all developmental and infection stages, and is localized to the cytoplasm. Disruption of MoPAH1 causes pleiotropic defects in vegetative growth, sporulation, and heat tolerance. The lipid profile is significantly altered in the Mopah1 mutant. Lipidomics assays showed that the level of phosphatidic acid (PA) was increased in the mutant, which had reduced levels of diacylglycerol and triacylglycerol. Using a PA biosensor, we showed that the increased level of PA in the Mopah1 mutant was primarily accumulated in the vacuole. The Mopah1 mutant was blocked in both conidiation and the formation of appressorium-like structures at hyphal tips. It was nonpathogenic and failed to cause any blast lesions on rice and barley seedlings. RNA sequencing analysis revealed that MoPah1 regulates the expression of transcription factors critical for various developmental and infection-related processes. The Mopah1 mutant was reduced in the expression and phosphorylation of Pmk1 MAP kinase and delayed in autophagy. Our study demonstrates that MoPah1 is necessary for lipid metabolism, fungal development, and pathogenicity in M. oryzae.

show abstract

An evolutionarily conserved phosphatidate phosphatase maintains lipid droplet number and ER morphology but not nuclear morphology

Cited by 15 publications

References 59 publications

Crystal structure of a lipin/Pah phosphatidic acid phosphatase

Crystal structure of a lipin/Pah phosphatidic acid phosphatase

Nuclear translocation ability of Lipin differentially affects gene expression and survival in fed and fasting Drosophila

The MoPah1 phosphatidate phosphatase is involved in lipid metabolism, development, and pathogenesis in Magnaporthe oryzae

Contact Info

Product

Resources

About