The structure and function of mammalian membrane-attack complex/perforin-like proteins

Kondos, S.C.; Hatfaludi, Tamas; Voskoboinik, Ilia; Trapani, Joseph A.; Law, Ruby H. P.; Whisstock, James C.; Dunstone, Michelle Anne

doi:10.1111/j.1399-0039.2010.01566.x

Cited by 63 publications

(54 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The perforins of cytotoxic T cells and natural killer cells and the membrane attack complex proteins of the complement system share the ability to form pores in membranes [1,2]. While the roles of these proteins in host defence are well understood, the function of the structurally related MPEG1/perforin-2 family in macrophages remains to be fully elucidated [3,9].…”

Section: Discussionmentioning

confidence: 99%

“…Membrane attack complex/perforin (MACPF) proteins belong to a large superfamily of pore-forming molecules present in almost all living organisms [1,2]. In vertebrates, MACPF proteins have crucial roles in immune defence against both extracellular and intracellular infections [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…In vertebrates, MACPF proteins have crucial roles in immune defence against both extracellular and intracellular infections [3,4]. The MACPF domain is present in the components of the terminal complement pathway (C6, C7, C8 and C9), which form the membrane attack complex (MAC) directly targeting gram-negative bacteria and certain pathogenic parasites by forming pores on their cell membranes [1]. The MACPF domain is also present in the perforins released by cytotoxic T lymphocytes and natural killer cells, which create pores in the plasma membranes of infected and transformed host cells, allowing the entry of cytolytic proteins [4].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Macrophage-Expressed Perforins Mpeg1 and Mpeg1.2 Have an Anti-Bacterial Function in Zebrafish

Benard¹,

Rácz²,

Rougeot³

et al. 2014

J Innate Immun

View full text Add to dashboard Cite

Macrophage-expressed gene 1 (MPEG1) encodes an evolutionarily conserved protein with a predicted membrane attack complex/perforin domain associated with host defence against invading pathogens. In vertebrates, MPEG1/perforin-2 is an integral membrane protein of macrophages, suspected to be involved in the killing of intracellular bacteria by pore-forming activity. Zebrafish have 3 copies of MPEG1; 2 are expressed in macrophages, whereas the third could be a pseudogene. The mpeg1 and mpeg1.2 genes show differential regulation during infection of zebrafish embryos with the bacterial pathogens Mycobacterium marinum and Salmonella typhimurium. While mpeg1 is downregulated during infection with both pathogens, mpeg1.2 is infection inducible. Upregulation of mpeg1.2 is partially dependent on the presence of functional Mpeg1 and requires the Toll-like receptor adaptor molecule MyD88 and the transcription factor NFκB. Knockdown of mpeg1 alters the immune response to M. marinum infection and results in an increased bacterial burden. In Salmonella typhimurium infection, both mpeg1 and mpeg1.2 knockdown increase the bacterial burdens, but mpeg1 morphants show increased survival times. The combined results of these two in vivo infection models support the anti-bacterial function of the MPEG1/perforin-2 family and indicate that the intricate cross-regulation of the two mpeg1 copies aids the zebrafish host in combatting infection of various pathogens.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Macrophage-Expressed Perforins Mpeg1 and Mpeg1.2 Have an Anti-Bacterial Function in Zebrafish

Benard¹,

Rácz²,

Rougeot³

et al. 2014

J Innate Immun

View full text Add to dashboard Cite

show abstract

“…As noted above, perforin plays a key role in immune surveillance because perforin pores enable delivery of lethal granzyme proteases into virus-infected or cancerous cells (Voskoboinik et al, 2015). The MACPF family is extremely diverse − its members function in immunity and pathogenesis across all kingdoms of life (Kondos et al, 2010). For example, MACPF proteins facilitate the invasion and/or proliferation of intracellular pathogens, such as Toxoplasma gondii, Plasmodium falciparum and Chlamydia, all of which must traverse cellular membrane barriers during their life cycles (Blackman and Carruthers, 2013;Taylor andNelson, 2014, Wade and.…”

Section: The Macpf-cdc Superfamilymentioning

confidence: 99%

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

Lukoyanova

Hoogenboom

Saibil

2016

Journal of Cell Science

View full text Add to dashboard Cite

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.

show abstract

“…Complement activation contributes to host defense through the opsonization of particles and the lysis of target cells through the assembly of the MAC, which is composed of complement proteins C5b-C9 (Kondos et al, 2010;Morgan, 2015). Complement activation also leads to inflammation, and people with genetic deficiencies in complement regulatory proteins frequently suffer from inflammatory immunopathology (Zipfel and Skerka, 2009).…”

Section: Introductionmentioning

confidence: 99%

Complement-mediated ‘bystander’ damage initiates host NLRP3 inflammasome activation

Suresh

Chandrasekaran

Sutterwala

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

Complement activation has long been associated with inflammation, primarily due to the elaboration of the complement anaphylotoxins C5a and C3a. In this work, we demonstrate that the phagocytosis of complement-opsonized particles promotes host inflammatory responses by a new mechanism that depends on the terminal complement components (C5b-C9). We demonstrate that during the phagocytosis of complement-opsonized particles, the membrane attack complex (MAC) of complement can be transferred from the activating particle to the macrophage plasma membrane by a 'bystander' mechanism. This MAC-mediated bystander damage initiates NLRP3 inflammasome activation, resulting in caspase-1 activation and IL-1β and IL-18 secretion. Inflammasome activation is not induced when macrophages phagocytize unopsonized particles or particles opsonized with serum deficient in one of the terminal complement components. The secretion of IL-1β and IL-18 by macrophages depends on NLRP3, ASC (also known as PYCARD) and caspase-1, as macrophages deficient in any one of these components fail to secrete these cytokines following phagocytosis. The phagocytosis of complement-opsonized particles increases leukocyte recruitment and promotes T helper 17 cell (T H 17) biasing. These findings reveal a new mechanism by which complement promotes inflammation and regulates innate and adaptive immunity.

show abstract

The structure and function of mammalian membrane-attack complex/perforin-like proteins

Cited by 63 publications

References 78 publications

Macrophage-Expressed Perforins Mpeg1 and Mpeg1.2 Have an Anti-Bacterial Function in Zebrafish

Macrophage-Expressed Perforins Mpeg1 and Mpeg1.2 Have an Anti-Bacterial Function in Zebrafish

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

Complement-mediated ‘bystander’ damage initiates host NLRP3 inflammasome activation

Contact Info

Product

Resources

About