TY - JOUR
T1 - Distinct role of Sirtuin 1 (SIRT1) and Sirtuin 2 (SIRT2) in inhibiting cargo-loading and release of extracellular vesicles
AU - Lee, Byung Rho
AU - Sanstrum, Bethany J.
AU - Liu, Yutao
AU - Kwon, Sang Ho
N1 - Funding Information:
We are grateful to Dr. Hyung Wook Lim (UCSF) for his intellectual contributions and to Dr. Graydon Gonsalvez for critical reading. This work was supported by NIH grant R01 DK120510 (S.-H.K.).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Exosomes, vehicles for intercellular communication, are formed intracellularly within multivesicular bodies (MVBs) and are released upon fusion with the plasma membrane. For their biogenesis, proper cargo loading to exosomes and vesicle traffic for extracellular release are required. Previously we showed that the L-type lectin, LMAN2, limits trans-Golgi Network (TGN)-to-endosomes traffic of GPRC5B, an exosome cargo protein, for exosome release. Here, we identified that the protein deacetylase sirtuin 2 (SIRT2) as a novel interactor of LMAN2. Loss of SIRT2 expression resulted in exosomal release of LMAN2, a Golgi resident protein, along with increased exosomal release of GPRC5B. Furthermore, knockout of SIRT2 increased total number of extracellular vesicles (EVs), indicating increased MVB-to-EV flux. While knockout of SIRT1 increased EV release with enlarged late endolysosome, knockout of SIRT2 did not exhibit endolysosome enlargement for increased EV release. Taken together, our study suggests that SIRT2 regulates cargo loading to MVBs and MVB-to-EV flux through a mechanism distinct from that of SIRT1.
AB - Exosomes, vehicles for intercellular communication, are formed intracellularly within multivesicular bodies (MVBs) and are released upon fusion with the plasma membrane. For their biogenesis, proper cargo loading to exosomes and vesicle traffic for extracellular release are required. Previously we showed that the L-type lectin, LMAN2, limits trans-Golgi Network (TGN)-to-endosomes traffic of GPRC5B, an exosome cargo protein, for exosome release. Here, we identified that the protein deacetylase sirtuin 2 (SIRT2) as a novel interactor of LMAN2. Loss of SIRT2 expression resulted in exosomal release of LMAN2, a Golgi resident protein, along with increased exosomal release of GPRC5B. Furthermore, knockout of SIRT2 increased total number of extracellular vesicles (EVs), indicating increased MVB-to-EV flux. While knockout of SIRT1 increased EV release with enlarged late endolysosome, knockout of SIRT2 did not exhibit endolysosome enlargement for increased EV release. Taken together, our study suggests that SIRT2 regulates cargo loading to MVBs and MVB-to-EV flux through a mechanism distinct from that of SIRT1.
UR - http://www.scopus.com/inward/record.url?scp=85077151481&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077151481&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-56635-0
DO - 10.1038/s41598-019-56635-0
M3 - Article
C2 - 31882861
AN - SCOPUS:85077151481
SN - 2045-2322
VL - 9
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 20049
ER -