TY - JOUR
T1 - LAMP2A regulates the loading of proteins into exosomes
AU - Ferreira, João Vasco
AU - da Rosa Soares, Ana
AU - Ramalho, José
AU - Máximo Carvalho, Catarina
AU - Cardoso, Maria Helena
AU - Pintado, Petra
AU - Carvalho, Ana Sofia
AU - Beck, Hans Christian
AU - Matthiesen, Rune
AU - Zuzarte, Mónica
AU - Girão, Henrique
AU - van Niel, Guillaume
AU - Pereira, Paulo
PY - 2022/3/25
Y1 - 2022/3/25
N2 - Exosomes are extracellular vesicles of endosomal origin that are released by practically all cell types across metazoans. Exosomes are active vehicles of intercellular communication and can transfer lipids, RNAs, and proteins between different cells, tissues, or organs. Here, we describe a mechanism whereby proteins containing a KFERQ motif pentapeptide are loaded into a subpopulation of exosomes in a process that is dependent on the membrane protein LAMP2A. Moreover, we demonstrate that this mechanism is independent of the ESCRT machinery but dependent on HSC70, CD63, Alix, Syntenin-1, Rab31, and ceramides. We show that the master regulator of hypoxia HIF1A is loaded into exosomes by this mechanism to transport hypoxia signaling to normoxic cells. In addition, by tagging fluorescent proteins with KFERQ-like sequences, we were able to follow the interorgan transfer of exosomes. Our findings open new avenues for exosome engineering by allowing the loading of bioactive proteins by tagging them with KFERQ-like motifs.
AB - Exosomes are extracellular vesicles of endosomal origin that are released by practically all cell types across metazoans. Exosomes are active vehicles of intercellular communication and can transfer lipids, RNAs, and proteins between different cells, tissues, or organs. Here, we describe a mechanism whereby proteins containing a KFERQ motif pentapeptide are loaded into a subpopulation of exosomes in a process that is dependent on the membrane protein LAMP2A. Moreover, we demonstrate that this mechanism is independent of the ESCRT machinery but dependent on HSC70, CD63, Alix, Syntenin-1, Rab31, and ceramides. We show that the master regulator of hypoxia HIF1A is loaded into exosomes by this mechanism to transport hypoxia signaling to normoxic cells. In addition, by tagging fluorescent proteins with KFERQ-like sequences, we were able to follow the interorgan transfer of exosomes. Our findings open new avenues for exosome engineering by allowing the loading of bioactive proteins by tagging them with KFERQ-like motifs.
KW - EXTRACELLULAR VESICLE
KW - DEGRADATION
KW - BIOGENESIS
KW - SYNTENIN
KW - LYSOSOMES
KW - SECRETION
U2 - 10.1126/sciadv.abm1140
DO - 10.1126/sciadv.abm1140
M3 - Article
C2 - 35333565
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 12
M1 - eabm1140
ER -