Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide

He, Qian; Wang, Guanghu; Wakade, Sushama; Dasgupta, Somsankar; Dinkins, Michael B.; Kong, Ji Na; Spassieva, Stefka D.; Bieberich, Erhard

doi:10.1091/mbc.e13-12-0730

Cited by 61 publications

(89 citation statements)

References 63 publications

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“…We have shown that excess cholesterol in RPE with vitamin A dimers activates ASMase, which interferes with organelle traffic by acetylating microtubules (MT) (20). To investigate how excess cholesterol and MT acetylation impacts CD59 trafficking, we treated RPE monolayers with either U18666A to increase cholesterol (25) and, thereby, acetylated MT (20), or with the HDAC6 inhibitor tubacin, which prevents MT deacetylation (26). Similar to A2E, both drugs decreased cell surface CD59 and increased MAC deposition after complement exposure (Fig.…”

Section: Resultsmentioning

confidence: 99%

Protective responses to sublytic complement in the retinal pigment epithelium

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Lakkaraju

2016

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

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The retinal pigment epithelium (RPE) is a key site of injury in inherited and age-related macular degenerations. Abnormal activation of the complement system is a feature of these blinding diseases, yet how the RPE combats complement attack is poorly understood. The complement cascade terminates in the cell-surface assembly of membrane attack complexes (MACs), which promote inflammation by causing aberrant signal transduction. Here, we investigated mechanisms crucial for limiting MAC assembly and preserving cellular integrity in the RPE and asked how these are compromised in models of macular degeneration. Using polarized primary RPE and the pigmented Abca4 −/− Stargardt disease mouse model, we provide evidence for two protective responses occurring within minutes of complement attack, which are essential for maintaining mitochondrial health in the RPE. First, accelerated recycling of the membrane-bound complement regulator CD59 to the RPE cell surface inhibits MAC formation. Second, fusion of lysosomes with the RPE plasma membrane immediately after complement attack limits sustained elevations in intracellular calcium and prevents mitochondrial injury. Cholesterol accumulation in the RPE, induced by vitamin A dimers or oxidized LDL, inhibits these defense mechanisms by activating acid sphingomyelinase (ASMase), which increases tubulin acetylation and derails organelle traffic. Defective CD59 recycling and lysosome exocytosis after complement attack lead to mitochondrial fragmentation and oxidative stress in the RPE. Drugs that stimulate cholesterol efflux or inhibit ASMase restore both these critical safeguards in the RPE and avert complement-induced mitochondrial injury in vitro and in Abca4 −/− mice, indicating that they could be effective therapeutic approaches for macular degenerations.he complement system is an important regulator of immunity and inflammation. Complement activation by the classical, alternative, or lectin pathways results in the assembly of C5b-9 membrane attack complexes (MACs), which form membrane pores and cause target cell lysis. Within the eye, a low level of constant complement activity is necessary for immune surveillance, and several membrane-bound and soluble regulators prevent excessive complement activation (1). An imbalance between complement activation and inhibition in the retina is implicated in the pathogenesis of age-related macular degeneration (AMD), which causes central vision loss in more than 30 million people globally (reviewed in refs. 2-4).Evidence suggests that the retinal pigment epithelium (RPE), which helps maintain ocular immune privilege, is the first line of defense against unregulated complement activation in the retina (5). The complement cascade is activated by insults that disturb RPE homeostasis, including defective clearance of phagocytosed photoreceptor outer segments (6) and abnormal accumulation of vitamin A dimers (7-9) or oxidized lipids (10) in the RPE. Studies also show that exposure to sublytic levels of MAC alters RPE barrier integrity, causes...

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Section: Resultsmentioning

confidence: 99%

Protective responses to sublytic complement in the retinal pigment epithelium

Tan

Toops

Lakkaraju

2016

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

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“…Despite this caveat, there is solid evidence from independent studies that ceramide binds directly to tubulin (20,28,29). Molecular modeling predicts that the affinity of tubulin for ceramide is relatively low (0.5-1 µM), which may turn CAT into a sensor for free tubulin at physiological levels in the cytosol to block VDAC1 and ATP release, provided that sufficient ceramide for CAT formation is available (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We showed that tubulin was coimmunoprecipitated when pulling down intracellular vesicles using anti-ceramide IgG (20). These studies suggested that ceramide may bind to free tubulin dispersed in the cytosol, or to tubulin embedded into microtubules or associated with cellular membranes (membrane tubulin).…”

Section: Introductionmentioning

confidence: 89%

“…Our earlier studies showed that tubulin was coimmunoprecipitated when pulling down intracellular vesicles using the anti-ceramide antibody (20). However, whether tubulin interacts directly with ceramide and what is the function of this potential interaction remained unclear.…”

Section: Tubulin Is Cross-linked To Pacfacer and Binds To Ceramidementioning

confidence: 99%

“…Increase of ceramide levels through upregulation of CerSs or SMases leads to induction of apoptosis and other cell signaling pathways critical for cell death, senescence, autophagy, or cell cycle arrest. We and others showed that the localized generation or distribution of ceramide in ceramide microdomains (rafts) or more extended ceramide-enriched compartments (CECs) may have additional cellular functions of ceramide (16)(17)(18)(19)(20)(21)(22)(23). Instrumental to our studies was the generation of a ceramide-specific antibody originally developed in our laboratory (24).…”

Section: Introductionmentioning

confidence: 99%

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Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes

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Journal of Lipid Research

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Sphingolipids controlling ciliary and microvillar function

2020

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Cilia and microvilli are membrane protrusions that extend from the surface of many different mammalian cell types. Motile cilia or flagella are only found on specialized cells, where they control cell movement or the generation of fluid flow, whereas immotile primary cilia protrude from the surface of almost every mammalian cell to detect and transduce extracellular signals. Despite these differences, all cilia consist of a microtubule core called the axoneme. Microvilli instead contain bundled linear actin filaments and are mainly localized on epithelial cells, where they modulate the absorption of nutrients. Cilia and microvilli constitute subcellular compartments with distinctive lipid and protein repertoires and specialized functions. Here, we summarize the role of sphingolipids in defining the identity and controlling the function of cilia and microvilli in mammalian cells.

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Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide

Cited by 61 publications

References 63 publications

Protective responses to sublytic complement in the retinal pigment epithelium

Protective responses to sublytic complement in the retinal pigment epithelium

Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes

Sphingolipids controlling ciliary and microvillar function

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