Palmitoylation of Progressive Rod-Cone Degeneration (PRCD) Regulates Protein Stability and Localization

Murphy, Joseph; Kolandaivelu, Saravanan

doi:10.1074/jbc.m116.742767

Cited by 23 publications

(43 citation statements)

References 41 publications

(46 reference statements)

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“…The mechanism appears rather 15 complicated as loss of dZDHHC8 leads to destabilization of Ras64B. It has been proposed for other proteins that lack of palmitoylation can lead to their destabilization [28,29]. In this case here it is unclear whether Ras64B destabilization is due to impaired palmitoylation or whether dZDHHC8 acts on Ras64B in a different manner to affect its stability, and as a consequence we also see reduced palmitoylation.…”

Section: Discussionmentioning

confidence: 62%

Drosophila ZDHHC8 palmitoylates scribble and Ras64B and controls growth and viability

Straßburger

Kang

Teleman

2018

Preprint

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SummaryPalmitoylation is an important posttranslational modification regulating diverse cellular functions. Consequently, aberrant palmitoylation can lead to diseases such as neuronal disorders or cancer. In humans there are roughly one hundred times more palmitoylated proteins than enzymes catalyzing palmitoylation (palmitoyltransferases). Therefore, it is an important challenge to establish the links between palmitoyltransferases and their targets. From publicly available data, we find that expression of human ZDHHC8 correlates significantly with cancer survival. To elucidate the organismal function of ZDHHC8, we study the Drosophila ortholog of hZDHHC8, CG34449/dZDHHC8. Knockdown of dZDHHC8 causes tissue overgrowth while dZDHHC8 mutants are larval lethal. We provide a list of 159 palmitoylated proteins in Drosophila and present data suggesting that scribble and Ras64B are targets of dZDHHC8.

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Section: Discussionmentioning

confidence: 62%

Drosophila ZDHHC8 palmitoylates scribble and Ras64B and controls growth and viability

Straßburger

Kang

Teleman

2018

Preprint

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“…Although such a detailed level of ultrastructural analysis has not been performed before, many phenotypic features of Prcd −/− mice parallel those associated with the C2Y PRCD mutation in dogs. This is not surprising because this mutation was shown to completely mislocalize PRCD from the outer segment, resulting in PRCD degradation, an effective knockout of the protein (14,15). As in dogs and humans containing a single allele of mutant PRCD, Prcd +/− mice do not display any overt phenotype, consistent with a truly recessive disease pattern.…”

Section: Discussionmentioning

confidence: 94%

“…PRCD is constitutively bound to rhodopsin with the C terminus exposed at the cytosolic disc surface and the N terminus S-acylated at the exact cysteine residue (C2) that is mutated to tyrosine in blind patients (14). The C2Y mutation in PRCD completely mislocalizes it from photoreceptor discs and results in PRCD degradation, which is functionally equivalent to a null mutation (14,15).…”

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confidence: 99%

PRCD is essential for high-fidelity photoreceptor disc formation

Spencer

Ding

Lewis

et al. 2019

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

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Progressive rod-cone degeneration (PRCD) is a small protein residing in the light-sensitive disc membranes of the photoreceptor outer segment. Until now, the function of PRCD has remained enigmatic despite multiple demonstrations that its mutations cause blindness in humans and dogs. Here, we generated a PRCD knockout mouse and observed a striking defect in disc morphogenesis, whereby newly forming discs do not properly flatten. This leads to the budding of disc-derived vesicles, specifically at the site of disc morphogenesis, which accumulate in the interphotoreceptor matrix. The defect in nascent disc flattening only minimally alters the photoreceptor outer segment architecture beyond the site of new disc formation and does not affect the abundance of outer segment proteins and the photoreceptor’s ability to generate responses to light. Interestingly, the retinal pigment epithelium, responsible for normal phagocytosis of shed outer segment material, lacks the capacity to clear the disc-derived vesicles. This deficiency is partially compensated by a unique pattern of microglial migration to the site of disc formation where they actively phagocytize vesicles. However, the microglial response is insufficient to prevent vesicular accumulation and photoreceptors of PRCD knockout mice undergo slow, progressive degeneration. Taken together, these data show that the function of PRCD is to keep evaginating membranes of new discs tightly apposed to each other, which is essential for the high fidelity of photoreceptor disc morphogenesis and photoreceptor survival.

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“…Immunofluorescent staining. After enucleation, mouse eyes were prepared as described previously 17 .…”

Section: Methodsmentioning

confidence: 99%

Loss of PRCD alters number and packaging density of rhodopsin in rod photoreceptor disc membranes

Sechrest

Murphy

Senapati

et al. 2020

Sci Rep

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Progressive rod-cone degeneration (PRCD) is a small protein localized to photoreceptor outer segment (OS) disc membranes. Several mutations in PRCD are linked to retinitis pigmentosa (RP) in canines and humans, and while recent studies have established that PRCD is required for high fidelity disc morphogenesis, its precise role in this process remains a mystery. To better understand the part which PRCD plays in disease progression as well as its contribution to photoreceptor OS disc morphogenesis, we generated a Prcd-KO animal model using CRISPR/Cas9. Loss of PRCD from the retina results in reduced visual function accompanied by slow rod photoreceptor degeneration. We observed a significant decrease in rhodopsin levels in Prcd-KO retina prior to photoreceptor degeneration. Furthermore, ultrastructural analysis demonstrates that rod photoreceptors lacking PRCD display disoriented and dysmorphic OS disc membranes. Strikingly, atomic force microscopy reveals that many disc membranes in Prcd-KO rod photoreceptor neurons are irregular, containing fewer rhodopsin molecules and decreased rhodopsin packing density compared to wild-type discs. This study strongly suggests an important role for PRCD in regulation of rhodopsin incorporation and packaging density into disc membranes, a process which, when dysregulated, likely gives rise to the visual defects observed in patients with PRCD-associated RP.

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Palmitoylation of Progressive Rod-Cone Degeneration (PRCD) Regulates Protein Stability and Localization

Cited by 23 publications

References 41 publications

Drosophila ZDHHC8 palmitoylates scribble and Ras64B and controls growth and viability

Drosophila ZDHHC8 palmitoylates scribble and Ras64B and controls growth and viability

PRCD is essential for high-fidelity photoreceptor disc formation

Loss of PRCD alters number and packaging density of rhodopsin in rod photoreceptor disc membranes

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