Distinct role of Sirtuin 1 (SIRT1) and Sirtuin 2 (SIRT2) in inhibiting cargo-loading and release of extracellular vesicles

Abstract

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.

Sirt1 during childhood is associated with microvascular function later in life

“…Interestingly, Sirt1 has been measured in circulation (30,39,41,72), although its precise origin and its relationship to tissue content have yet to be completely elucidated. A possibility is that Sirt1 is secreted as part of extracellular vesicles, which is not surprising considering that proteins packaged into these vesicles are part of the mechanisms of biogenesis, and Sirt1 has a critical role in exosome secretion and lysosome function (33)(34)(35)45). This hypothesis has been supported by previous experiments that demonstrated the presence of another sirtuin in exosomes from oligodendroglial cells (16).…”

The Regulatory Effect of SIRT1 on Extracellular Microenvironment Remodeling

“…A recent study exhibits that inhibition of SIRT1 by caveolin-1 in senescent fibroblasts promotes the secretion of interleukin 6 (IL-6) and stimulates tumor growth [110]. The latest progress discovers that SIRT1 is responsible for the change of microenvironment by regulating the secretion of exosomes [111] (Fig. 4).…”

“…The latest progress discovers that SIRT1 is responsible for the change of microenvironment by regulating the secretion of exosomes 111 (Fig. 4 ).…”

Pharmacological inhibition of nSMase2 reduces brain exosome release and α-synuclein pathology in a Parkinson’s disease model

“…Lee et al . showed that loss of SirT2 expression also increased the total number of EVs, albeit by a separate suggested mechanism than that of SirT1 [ 55 ]. Others have also reported an association between loss of SirT1 and increased EV/exosome release [ 56 ].…”