![]() However, there is as yet no evidence that exosomes cannot bud from the plasma membrane, and there is significant evidence that plasma membranes can be a major site for budding of exosomal proteins, lipids, and their associated carbohydrates (Booth et al., 2006 Fang et al., 2007 Krishnamoorthy et al., 2009 Marsh et al., 2009 ). In this view, microvesicles bud from the plasma membrane, whereas exosomes are secreted by a two-step process in which vesicles 1) bud at endosomes to form multivesicular bodies (MVBs) and 2) are subsequently released after the fusion of MVBs with the plasma membrane. It has been proposed that cells secrete small vesicles by two separate mechanisms, microvesicle biogenesis and exosome biogenesis (Cocucci et al., 2009 Simons and Raposo, 2009 ). In addition, there is increasing evidence that these secreted vesicles play important roles in both normal physiological processes, such as immune signaling (Thery et al., 2009 ) and development (Liegeois et al., 2006 Kolotuev et al., 2009 ), as well as in diseases such as cancer (Yu et al., 2006 Yu et al., 2009 Keller et al., 2009 ), viral infections (Dukers et al., 2000 Gould et al., 2003 Fang et al., 2007 Logozzi et al., 2009 Nazarenko et al., 2010 ), and amyloidopathies (Fevrier et al., 2004 Leblanc et al., 2006 Alais et al., 2008 ). These vesicles mediate the release of specific proteins, lipids, mRNAs, and microRNAs transmit signals to neighboring cells and traffic molecules from the cytoplasm and membranes of one cell to the cytoplasm and membranes of others (Thery et al., 2002 Valadi et al., 2007 Skog et al., 2008 Simons and Raposo, 2009 ). Taken together, these results demonstrate that inhibitory signals can block protein and virus budding, raise the possibility that the ESCRT machinery plays a role in EMV biogenesis, and shed new light on the role of the p6 domain and PTAP motif in the biogenesis of HIV particles.Īnimal cells release small single-membrane vesicles (∼50–250 nm) that have the same topology as the cell (Trams et al., 1981 Pan and Johnstone, 1983 Gould et al., 2003 Fang et al., 2007 Schorey and Bhatnagar, 2008 Cocucci et al., 2009 Simons and Raposo, 2009 Thery et al., 2009 ). However, the IBS does inhibit an interaction between EMV cargo proteins and VPS4B, a component of the endosomal sorting complexes required for transport (ESCRT) machinery. The IBS does not prevent cargo delivery to the plasma membrane, a major site of EMV and virus budding. This IBS also impairs the budding of CD63 and several other viral and nonviral EMV proteins. This IBS was identified in the spacer peptide 2 (SP2) domain of Gag, is activated by C-terminal exposure of SP2, and mediates the severe budding defect of p6-deficient and PTAP-deficient strains of HIV. Here we describe an inhibitory budding signal (IBS) from the human immunodeficiency virus (HIV) Gag protein. The combination of higher-order oligomerization and plasma membrane binding is a positive budding signal that targets diverse proteins into EMVs and retrovirus particles. Animal cells bud exosomes and microvesicles (EMVs) from endosome and plasma membranes.
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