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Post-translational modifications of exosomal proteins.

Moreno-Gonzalo O, Villarroya-Beltri C, Sánchez-Madrid F - Front Immunol (2014)

Bottom Line: Exosomes mediate intercellular communication and participate in many cell processes such as cancer progression, immune activation or evasion, and the spread of infection.However, the mechanisms that control the sorting of protein cargo into exosomes are currently elusive.Here, we review the post-translational modifications detected in exosomal proteins, and discuss their possible role in their specific sorting into exosomes.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology and Inflammation Department, Centro Nacional de Investigaciones Cardiovasculares , Madrid , Spain ; Servicio de Inmunología, Hospital de la Princesa, Instituto de Investigación Sanitaria de la Princesa, Universidad Autónoma de Madrid , Madrid , Spain.

ABSTRACT
Exosomes mediate intercellular communication and participate in many cell processes such as cancer progression, immune activation or evasion, and the spread of infection. Exosomes are small vesicles secreted to the extracellular environment through the release of intraluminal vesicles contained in multivesicular bodies (MVBs) upon the fusion of these MVBs with the plasma membrane. The composition of exosomes is not random, suggesting that the incorporation of cargo into them is a regulated process. However, the mechanisms that control the sorting of protein cargo into exosomes are currently elusive. Here, we review the post-translational modifications detected in exosomal proteins, and discuss their possible role in their specific sorting into exosomes.

No MeSH data available.


Related in: MedlinePlus

Post-translational modifications of exosomal proteins. Membrane receptors such as EGFR and MHCII are ubiquitinated and sorted to MVBs. Then, they follow a degradative pathway by the fusion with lysosomes. Note that non-ubiquitinated-MHCII can be sorted into exosomes. Ubiquitinated LMP2A and ubiquitinated and phosphorylated FasL follow a secretory pathway where both modified proteins are delivered into exosomes. Non-membrane proteins like SUMOylated hnRNPA2B1, phosphorylated and oxidized γ-synuclein, and phosphorylated tau are packed into exosomes. Myristoylated TyA protein is able to oligomerize, leading to the formation of shedding vesicles. Ubiquitinated ARRDC1 can induce plasma membrane budding by an ESCRT complex-depending mechanism, producing ectosomes.
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Figure 1: Post-translational modifications of exosomal proteins. Membrane receptors such as EGFR and MHCII are ubiquitinated and sorted to MVBs. Then, they follow a degradative pathway by the fusion with lysosomes. Note that non-ubiquitinated-MHCII can be sorted into exosomes. Ubiquitinated LMP2A and ubiquitinated and phosphorylated FasL follow a secretory pathway where both modified proteins are delivered into exosomes. Non-membrane proteins like SUMOylated hnRNPA2B1, phosphorylated and oxidized γ-synuclein, and phosphorylated tau are packed into exosomes. Myristoylated TyA protein is able to oligomerize, leading to the formation of shedding vesicles. Ubiquitinated ARRDC1 can induce plasma membrane budding by an ESCRT complex-depending mechanism, producing ectosomes.

Mentions: Ubiquination, thus denotes a complex network of PTMs, and its role in the sorting of proteins into exosomes is far from understood. There seems to be consensus that ubiquitination is necessary for sorting proteins into ILVs destined for degradation through the fusion of the encompassing MVB with lysosomes. This process is mediated by the endosomal sorting complex required for transport machinery (ESCRT complex) and affects proteins such as epithelial growth factor receptor (EGFR) (38) (Figure 1). This machinery recognizes ubiquitinated cargoes and catalyzes the abscission of endosomal invaginations, forming ILVs that contain the sorted cargo [reviewed in Raiborg and Stenmark (39)]. The ESCRT complex consists of four subcomplexes, ESCRT-0, -I, -II, and -III, and several accessory proteins. ESCRT-0, -I, and -II contain ubiquitin-binding subunits that interact directly with ubiquitinated cargo. The directional flow of cargo from ESCRT-0 to ESCRT-I and -II might be regulated by PTMs. In fact, the ESCRT-0 subunits are known to be phosphorylated and to be mono-ubiquitinated (40–42). The latter modification keeps these subunits in an inactive form owing to intramolecular interactions between their ubiquitin interacting motifs and the appended ubiquitin (43, 44). However, the role of ubiquitin and the ESCRT complex in the sorting of proteins into ILVs for exosome secretion is still unclear, and MVB biogenesis, exosome secretion, and exosomal-protein sorting have been reported in an ESCRT/ubiquitin-independent manner [reviewed at Villarroya-Beltri et al. (45)].


Post-translational modifications of exosomal proteins.

Moreno-Gonzalo O, Villarroya-Beltri C, Sánchez-Madrid F - Front Immunol (2014)

Post-translational modifications of exosomal proteins. Membrane receptors such as EGFR and MHCII are ubiquitinated and sorted to MVBs. Then, they follow a degradative pathway by the fusion with lysosomes. Note that non-ubiquitinated-MHCII can be sorted into exosomes. Ubiquitinated LMP2A and ubiquitinated and phosphorylated FasL follow a secretory pathway where both modified proteins are delivered into exosomes. Non-membrane proteins like SUMOylated hnRNPA2B1, phosphorylated and oxidized γ-synuclein, and phosphorylated tau are packed into exosomes. Myristoylated TyA protein is able to oligomerize, leading to the formation of shedding vesicles. Ubiquitinated ARRDC1 can induce plasma membrane budding by an ESCRT complex-depending mechanism, producing ectosomes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128227&req=5

Figure 1: Post-translational modifications of exosomal proteins. Membrane receptors such as EGFR and MHCII are ubiquitinated and sorted to MVBs. Then, they follow a degradative pathway by the fusion with lysosomes. Note that non-ubiquitinated-MHCII can be sorted into exosomes. Ubiquitinated LMP2A and ubiquitinated and phosphorylated FasL follow a secretory pathway where both modified proteins are delivered into exosomes. Non-membrane proteins like SUMOylated hnRNPA2B1, phosphorylated and oxidized γ-synuclein, and phosphorylated tau are packed into exosomes. Myristoylated TyA protein is able to oligomerize, leading to the formation of shedding vesicles. Ubiquitinated ARRDC1 can induce plasma membrane budding by an ESCRT complex-depending mechanism, producing ectosomes.
Mentions: Ubiquination, thus denotes a complex network of PTMs, and its role in the sorting of proteins into exosomes is far from understood. There seems to be consensus that ubiquitination is necessary for sorting proteins into ILVs destined for degradation through the fusion of the encompassing MVB with lysosomes. This process is mediated by the endosomal sorting complex required for transport machinery (ESCRT complex) and affects proteins such as epithelial growth factor receptor (EGFR) (38) (Figure 1). This machinery recognizes ubiquitinated cargoes and catalyzes the abscission of endosomal invaginations, forming ILVs that contain the sorted cargo [reviewed in Raiborg and Stenmark (39)]. The ESCRT complex consists of four subcomplexes, ESCRT-0, -I, -II, and -III, and several accessory proteins. ESCRT-0, -I, and -II contain ubiquitin-binding subunits that interact directly with ubiquitinated cargo. The directional flow of cargo from ESCRT-0 to ESCRT-I and -II might be regulated by PTMs. In fact, the ESCRT-0 subunits are known to be phosphorylated and to be mono-ubiquitinated (40–42). The latter modification keeps these subunits in an inactive form owing to intramolecular interactions between their ubiquitin interacting motifs and the appended ubiquitin (43, 44). However, the role of ubiquitin and the ESCRT complex in the sorting of proteins into ILVs for exosome secretion is still unclear, and MVB biogenesis, exosome secretion, and exosomal-protein sorting have been reported in an ESCRT/ubiquitin-independent manner [reviewed at Villarroya-Beltri et al. (45)].

Bottom Line: Exosomes mediate intercellular communication and participate in many cell processes such as cancer progression, immune activation or evasion, and the spread of infection.However, the mechanisms that control the sorting of protein cargo into exosomes are currently elusive.Here, we review the post-translational modifications detected in exosomal proteins, and discuss their possible role in their specific sorting into exosomes.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology and Inflammation Department, Centro Nacional de Investigaciones Cardiovasculares , Madrid , Spain ; Servicio de Inmunología, Hospital de la Princesa, Instituto de Investigación Sanitaria de la Princesa, Universidad Autónoma de Madrid , Madrid , Spain.

ABSTRACT
Exosomes mediate intercellular communication and participate in many cell processes such as cancer progression, immune activation or evasion, and the spread of infection. Exosomes are small vesicles secreted to the extracellular environment through the release of intraluminal vesicles contained in multivesicular bodies (MVBs) upon the fusion of these MVBs with the plasma membrane. The composition of exosomes is not random, suggesting that the incorporation of cargo into them is a regulated process. However, the mechanisms that control the sorting of protein cargo into exosomes are currently elusive. Here, we review the post-translational modifications detected in exosomal proteins, and discuss their possible role in their specific sorting into exosomes.

No MeSH data available.


Related in: MedlinePlus