Optineurin tunes outside-in signaling to regulate lysosome biogenesis and phagocytic clearance in the retina

Tan, Li Xuan; Germer, Colin J.; Thamban, Thushara; Cunza, Nilsa La; Lakkaraju, Aparna

doi:10.1016/j.cub.2023.07.031

Cited by 9 publications

(6 citation statements)

References 67 publications

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“…The ability of the RPE to maintain lipid balance and regulate the fate of its intracellular lipid pool is central not only RPE function but also photoreceptor function. 8,53 The RPE intracellular lipid pool is fed by the daily phagocytosis and processing of polyunsaturated lipid rich OS and is augmented with the de novo synthesis of lipids as well as the uptake of Blps from the systemic circulation as illustrated in Figure 11. The studies herein point to MTP-mediated Blp assembly in the RPE as an essential pathway in maintaining a healthy lipid balance between the RPE and PR and, hence, cell function (for review Ref.…”

Section: Discussionmentioning

confidence: 99%

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

Grubaugh,

Dhingra,

Prakash

et al. 2024

The FASEB Journal

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Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or age‐related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (APOB)‐containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generated RPEΔMttp mouse model. Using non‐invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic depletion of Mttp from the RPE results in intracellular lipid accumulation, increased photoreceptor‐associated cholesterol deposits, and photoreceptor cell death, and loss of rod but not cone function. RPE‐specific reduction in Mttp had no significant effect on plasma lipids and lipoproteins. While APOB was decreased in the RPE, most ocular retinoids remained unchanged, with the exception of the storage form of retinoid, retinyl ester. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but is not directly involved in plasma lipoprotein metabolism. These studies demonstrate that RPE‐specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function.

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Section: Discussionmentioning

confidence: 99%

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

Grubaugh,

Dhingra,

Prakash

et al. 2024

The FASEB Journal

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show abstract

“…However, both cathepsin D expression and phagolysosomal degradation of outer segments are unimpaired in Grn −/− RPE. This is not surprising because efficient outer segment phagocytosis by the RPE is fundamental to photoreceptor health and vision and the RPE has robust mechanisms to safeguard this process even under conditions of significant cellular stress 68 . Providing further proof of this, high-resolution imaging revealed that subretinal microglia had phagocytosed photoreceptor outer segments and that it was these microglia, and not the RPE, that were the source of age-dependent lipofuscin autofluorescence.…”

Section: Discussionmentioning

confidence: 99%

“…In some studies, the C3aR inhibitor SB290157 was administered intraperitoneally (0.5 mg/kg) to 1-month-old mice 3 times/week for 8 weeks. Depending on the experimental paradigm, mice of various ages were euthanized using CO 2 asphyxiation, eyes were removed, and eyecups were processed for immunohistochemistry, live imaging, immunoblotting, or transcriptomics as previously detailed 30,45,68,90,91 . All studies were approved by University of California, San Francisco animal care and use authorities and in accordance to ARRIVE guidelines.…”

Section: Star Methodsmentioning

confidence: 99%

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Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia

Tan,

Oertel,

Cheng

et al. 2024

Preprint

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SUMMARYMutations in progranulin (GRN) cause frontotemporal dementia (GRN-FTD) due to deficiency of the pleiotropic protein progranulin.GRN-FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging ofGRN-FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise,Grn−/−mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) inGrn−/−RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

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“…The ability of the RPE to maintain lipid balance and regulate the fate of its intracellular lipid pool is central not only to RPE but also photoreceptor function. The RPE intracellular lipid pool is fed by OS derived lipids through the daily ingestion of OS fragments by the RPE, in process historically referred to as phagocytosis but recently called trogocytosis (8, 48). We have retained the term phagocytosis herein.…”

Section: Discussionmentioning

confidence: 99%

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

Grubaugh,

Dhingra,

Prakash

et al. 2023

Preprint

View full text Add to dashboard Cite

Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or to age-related disease triggers lipid accumulation within the RPE, on Bruch’s membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (apoB)-containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by theMTTPgene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generatedRPEΔMttpmouse model. Using non-invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic deletion ofMttpfrom the RPE results in intracellular lipid accumulation, increased photoreceptor –associated cholesterol deposits and photoreceptor cell death, and loss of rod but not cone function. RPE-specific ablation of Mttp had no significant effect on plasma lipids and lipoproteins. While, apoB was decreased in the RPE, ocular retinoid concentrations remained unchanged. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but not directly involved in ocular retinoid and plasma lipoprotein metabolism. These studies demonstrate that RPE-specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function.

show abstract

Optineurin tunes outside-in signaling to regulate lysosome biogenesis and phagocytic clearance in the retina

Cited by 9 publications

References 67 publications

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

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