The Making of a Macromolecular Machine: Assembly of the Membrane Attack Complex

Bubeck, Doryen

doi:10.1021/bi500157z

Cited by 63 publications

(44 citation statements)

References 80 publications

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“…We further hypothesize that the secreted perforins insert into the epithelial cell membrane to form hetero-oligomeric pores, similar to the hetero-oligomeric membrane attack complex formed by complement proteins C5b-C9 (reviewed in Ref. [38]). Noteworthy, recent data on the PPLP family have shown that these are present in multiple life-cycle stages of the malaria parasite.…”

Section: Resultsmentioning

confidence: 95%

Perforin-like protein PPLP4 is crucial for mosquito midgut infection by Plasmodium falciparum

Wirth

Bennink

Scheuermayer

et al. 2015

Molecular and Biochemical Parasitology

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The genomes of Plasmodium parasites encode for five perforin-like proteins, PPLP1-5, and four of them have previously been demonstrated to be involved in disruption of host cell barriers. We now show that the fifth perforin, PPLP4, is crucial for infection of the mosquito vector by Plasmodium falciparum parasites. PPLP4 is expressed in the blood and mosquito midgut stages in granular structures. In gametocytes, PPLP4 expression is specific to the female gender, while ookinetes show a PPLP4 localization at the apical pole. Gene disruption of pplp4 results in no phenotypical change during blood stage replication, gametocyte development or gametogenesis, while mosquitoes fed with PPLP4-deficient gametocytes display a severe reduction in oocyst numbers, and an accumulation of ookinetes in the mosquito midguts was observed. In conclusion, we propose an essential role for PPLP4 in infection of the mosquito midgut, presumably by mediating ookinete traversal through the midgut epithelium.

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Section: Resultsmentioning

confidence: 95%

Perforin-like protein PPLP4 is crucial for mosquito midgut infection by Plasmodium falciparum

Wirth

Bennink

Scheuermayer

et al. 2015

Molecular and Biochemical Parasitology

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“…Structural studies show that C5b-8 on the membrane induces conformational changes in CD59 that enable the latter to bind to C9 and inhibit MAC formation (15). Thus, only CD59 on the cell surface can respond to C5b-8, suggesting that sublytic complement attack could modulate CD59 recycling.…”

Section: Resultsmentioning

confidence: 99%

“…The alternative pathway of complement activation begins with the spontaneous hydrolysis of C3 and sequential recruitment of C5b, C6, C7, C8, and finally C9, which polymerizes to form the MAC (2). The membrane-bound complement regulator CD59, which binds C8 and C9, prevents recruitment of C9 to the C5b-8 complex and thus inhibits the final step of MAC assembly (15). Immunostaining of human donor tissue shows that CD59 is predominantly found on the apical surface (16).…”

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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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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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“…The complement system was discovered over a century ago by the immunologist Jules Bordet, who described it as the ability of blood plasma factors to lyse bacteria. It is now understood that the complement system involves a cascade of activation reactions that ultimately triggers pore formation by the C9 complement component of the MAC (Bubeck, 2014;Merle et al, 2015). In the 1980s, a related pore-forming protein, perforin, was characterised in cytotoxic T-lymphocytes and natural killer cells in the blood (Podack and Dennert, 1983;McCormack et al, 2013).…”

Section: The Macpf-cdc Superfamilymentioning

confidence: 99%

“…1B). For the MAC, the main pore-forming component C9 binds to the target membrane through a complex that comprises six other MAC componentsC5b (a product of cleavage of C5), C6, C7 and C8 -with the latter comprising the two MACPF proteins C8α and C8β, and the non-MACPF protein C8γ (Bubeck, 2014;Merle et al, 2015). It has been shown that this MAC complex comprising C5b-C8 is capable of forming transmembrane pores and lysing cells in the absence of C9 (Ramm et al, 1982;Morgan et al, 1986), but the structural details and biological relevance of these lesions remain to be understood.…”

Section: Macpf-cdc Pore Formationmentioning

confidence: 99%

The membrane attack complex, perforin and cholesterol-dependent cytolysin superfamily of pore-forming proteins

Lukoyanova

Hoogenboom

Saibil

2016

Journal of Cell Science

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The membrane attack complex and perforin proteins (MACPFs) and bacterial cholesterol-dependent cytolysins (CDCs) are two branches of a large and diverse superfamily of pore-forming proteins that function in immunity and pathogenesis. During pore formation, soluble monomers assemble into large transmembrane pores through conformational transitions that involve extrusion and refolding of two α-helical regions into transmembrane β-hairpins. These transitions entail a dramatic refolding of the protein structure, and the resulting assemblies create large holes in cellular membranes, but they do not use any external source of energy. Structures of the membrane-bound assemblies are required to mechanistically understand and modulate these processes. In this Commentary, we discuss recent advances in the understanding of assembly mechanisms and molecular details of the conformational changes that occur during MACPF and CDC pore formation.

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The Making of a Macromolecular Machine: Assembly of the Membrane Attack Complex

Cited by 63 publications

References 80 publications

Perforin-like protein PPLP4 is crucial for mosquito midgut infection by Plasmodium falciparum

Perforin-like protein PPLP4 is crucial for mosquito midgut infection by Plasmodium falciparum

Protective responses to sublytic complement in the retinal pigment epithelium

The membrane attack complex, perforin and cholesterol-dependent cytolysin superfamily of pore-forming proteins

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