Yeast ENV9 encodes a conserved lipid droplet (LD) short-chain dehydrogenase involved in LD morphology

Siddiqah, Ikha M.; Manandhar, Surya P.; Cocca, Stephanie M.; Hsueh, Teli; Cervantes, Vanessa; Gharakhanian, Editte

doi:10.1007/s00294-017-0702-y

Cited by 13 publications

(16 citation statements)

References 81 publications

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“…74 In vitro site-directed mutagenesis that abolishes the oxidoreductase activity of ENV9, an ortholog of human RDH12, suggests a role for the enzyme in the formation of lipid droplets. 75 It is possible that the central retina may be particularly susceptible to degeneration due to higher demands for retinoids, particularly by cone photoreceptors. 16,76 Most variants reported in the current work are predicted to cause lack-of-function proteins.…”

Section: Discussionmentioning

confidence: 99%

RDH12Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function

Alemán

Uyhazi

Serrano

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To describe the retinal phenotype of pediatric patients with mutations in the retinol dehydrogenase 12 (RDH12) gene. METHODS. Twenty-one patients from 14 families (ages 2-17 years) with RDH12-associated inherited retinal degeneration (RDH12-IRD) underwent a complete ophthalmic exam and imaging with spectral domain optical coherence tomography (SD-OCT) and near infrared and short-wavelength fundus autofluorescence. Visual field extent was measured with Goldmann kinetic perimetry, visual thresholds with dark-adapted static perimetry or with dark-adapted chromatic full-field stimulus testing (FST) and transient pupillometry. RESULTS. Visual acuity ranged from 20/40 to light perception. There was parafoveal depigmentation or atrophic maculopathies accompanied by midperipheral intraretinal pigment migration. SD-OCT revealed foveal thinning in all patients and detectable but thinned outer nuclear layer (ONL) at greater eccentricities from the fovea. Photoreceptor outer segment (POS) signals were only detectable in small pockets within the central retina. Measurable kinetic visual fields were limited to small (<5-108) central islands of vision. Electroretinograms were reported as undetectable or severely reduced in amplitude. FST sensitivities to a 467 nm stimulus were rod-mediated and reduced on average by~2.5 log units. A thinned central ONL colocalized with severely reduced to nondetectable conemediated sensitivities. Pupillometry confirmed the psychophysically measured abnormalities. CONCLUSIONS. RDH12-IRD causes an early-onset, retina-wide disease with particularly severe central retinal abnormalities associated with relatively less severe rod photoreceptor dysfunction, a pattern consistent with an early-onset cone-rod dystrophy. Severely abnormal POS but detectable ONL in the pericentral and peripapillary retina suggest these regions may become targets for gene therapy.

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Section: Discussionmentioning

confidence: 99%

RDH12Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function

Alemán

Uyhazi

Serrano

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…CG2064, CG2065, and CG9360 belong to the NADP(H)‐dependent short‐chain dehydrogenase/reductase (SDR) family and are up‐regulated more than 3‐fold in CSN2 or CSN7 RNAi. SDR is a large protein superfamily and two SDR subfamilies, hydroxysteroid dehydrogenase (HSD) and RDH, have been reported to regulate lipid droplet dynamics (Deisenroth et al , 2011 ; Adams et al , 2014 ; Siddiqah et al , 2017 ; Yang et al , 2018 ). CG2064 and CG2065 belong to the RDH subfamily.…”

Section: Resultsmentioning

confidence: 99%

“…RDH12 is localized on the ER and its activity modulates retinol homeostasis (Keller & Adamski, 2007 ). ENV9, the yeast homolog of RDH12, increases lipid droplet size in a reductase activity‐dependent manner (Siddiqah et al , 2017 ). Therefore, we first examined whether the enzymatic activity of RDH/CG2064 is required for lipid droplet size regulation.…”

Section: Resultsmentioning

confidence: 99%

“…RDH/CG2064 is a member of SDR, a large enzyme superfamily mainly defined by a similar three‐dimensional structure and catalytic amino acid tetrad. RDH and HSD, two SDR subfamilies, have been linked to lipid droplets or lipid storage‐related diseases (Sandell et al , 2007 ; Deisenroth et al , 2011 ; Jiang & Napoli, 2013 ; Su et al , 2014 ; Siddiqah et al , 2017 ). Some of these proteins are localized on lipid droplets and regulate lipid droplet dynamics in either an enzymatic activity‐dependent or ‐independent manner.…”

Section: Discussionmentioning

confidence: 99%

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An RDH‐Plin2 axis modulates lipid droplet size by antagonizing Bmm lipase

et al. 2022

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The size of lipid droplets varies greatly in vivo and is determined by both intrinsic and extrinsic factors. From an RNAi screen in Drosophila, we found that knocking down subunits of COP9 signalosome (CSN) results in enlarged lipid droplets under high‐fat, but not normal, conditions. We identified CG2064, a retinol dehydrogenase (RDH) homolog, as the proteasomal degradation target of CSN in regulating lipid droplet size. RDH/CG2064 interacts with the lipid droplet‐resident protein Plin2 and the RDH/CG2064‐Plin2 axis acts to reduce the overall level and lipid droplet localization of Bmm/ATGL lipase. This axis is important for larval survival under prolonged starvation. Thus, we discovered an RDH‐Plin2 axis modulates lipid droplet size.

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“…Live cells were viewed by confocal microscopy at 1,8003 magnification and scored for prominent (1-3 vacuoles/cell) versus multilobed (.3 vacuoles/cell) vacuoles. For localization studies of GFP-tagged Env7, env7D cells transformed with plasmids expressing either GFP-tagged WT or mutant Env7 from an endogenous promoter were grown to an optical density at 600 nm of 0.8 in SM-URA, stained with FM4-64, and viewed by confocal microscopy as described previously (62). Images were equally enlarged to 34,000 and were analyzed and processed with Photoshop CS5.…”

Section: Microscopymentioning

confidence: 99%

A kinase cascade on the yeast lysosomal vacuole regulates its membrane dynamics: conserved kinase Env7 is phosphorylated by casein kinase Yck3

Manandhar

Siddiqah

Cocca

et al. 2020

Journal of Biological Chemistry

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Membrane fusion/fission is a highly dynamic and conserved process that responds to intra- and extracellular signals. While the molecular machineries involved in membrane fusion/fission have been dissected, regulation of membrane dynamics remains poorly understood. The lysosomal vacuole of budding yeast (Saccharomyces cerevisiae) has served as a seminal model in studies of membrane dynamics. We have previously established that yeast ENV7 encodes an ortholog of STK16-related kinases that localizes to the vacuolar membrane and down-regulates vacuolar membrane fusion. Additionally, we have previously reported that Env7 phosphorylation in vivo is dependent on YCK3, a gene that encodes a vacuolar membrane casein kinase I (CKI) homolog that non-redundantly functions in fusion regulation. Here, we report that Env7 physically interacts with and is directly phosphorylated by Yck3. We also establish that Env7 vacuole fusion/fission regulation and vacuolar localization are mediated through its Yck3-dependent phosphorylation. Through extensive site-directed mutagenesis, we map phosphorylation to the Env7 C terminus and confirm that Ser-331 is a primary and preferred phosphorylation site. Phospho-deficient Env7 mutants were defective in negative regulation of membrane fusion, increasing the number of prominent vacuoles, whereas a phospho-mimetic substitution at Ser-331 increased the number of fragmented vacuoles. Bioinformatics approaches confirmed that Env7 Ser-331 is within a motif that is highly conserved in STK16-related kinases and that it also anchors an SXXS CKI phosphorylation motif (328SRFS331). This study represents the first report on the regulatory mechanism of an STK16 related kinase. It also points to regulation of vacuolar membrane dynamics via a novel Yck3–Env7 kinase cascade.

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Yeast ENV9 encodes a conserved lipid droplet (LD) short-chain dehydrogenase involved in LD morphology

Cited by 13 publications

References 81 publications

RDH12Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function

RDH12Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function

An RDH‐Plin2 axis modulates lipid droplet size by antagonizing Bmm lipase

A kinase cascade on the yeast lysosomal vacuole regulates its membrane dynamics: conserved kinase Env7 is phosphorylated by casein kinase Yck3

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