Emission of membrane vesicles: roles in complement resistance, immunity and cancer.
Complement-mediated cell death is caused by C5b-9, the membrane attack complex (MAC) composed of the five complement proteins C5b, C6, C7, C8, and C9. Assembly of the C5b-9 complex initiates oligomerization of C9 and production of a transmembrane protein channel that inflicts damage to target cells. For protection, cells eliminate the MAC from their surface either by ectocytosis (direct emission of membrane vesicles) or by endocytosis (internalization). The process of ectosome release is rapid and involves cytosolic Ca(2+) and activation of protein kinases, such as protein kinase C (PKC) and extracellular signal-regulated protein kinase (ERK). Recently, the involvement of mortalin (also known as GRP75 and mitochondrial hsp70) in MAC elimination has been suggested. Extracellular application of antibodies directed to mortalin increases cell sensitivity to MAC-mediated lysis. Release of membrane vesicles is ubiquitous and enhanced in apoptotic or tumor cells and upon cell activation. Composition of the ectosomes (also often referred to as microparticles) membrane proteins and lipids appears to be different from those of the original plasma membrane, indicating involvement of a selective sorting process during ectosome formation. Exosomes (unlike ectosomes) are membrane vesicles generated by endocytosis, endosome sorting into perinuclear multivesicular bodies (MVB) and exocytosis of MVBs. Exosomes appear to be different in size and composition from ectosomes. Exosome-associated MAC has also been described. Although research on ectosomes and exosomes is still limited, physiological roles in coagulation, vascular functions, angiogenesis, wound healing and development have been attributed to these shed membrane vesicles. On the other hand, there are indications that elevated levels of ectosomes and exosomes may predispose to morbidity. Membrane vesicles released by cells exposed to complement MAC may play roles in health and disease beyond protection from cell death.
Pilzer
David
D
Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Gasser
Olivier
O
Moskovich
Oren
O
Schifferli
Jurg A
JA
Fishelson
Zvi
Z
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology*; D005089:Exocytosis / Q000276:immunology; D006801:Humans; D018448:Models, Immunological; D009369:Neoplasms / Q000276:immunology*; D022161:Transport Vesicles / Q000276:immunology
D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins