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제112회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Customized Mesoporous Silica Nanoparticles (MSN)-Mediated Proteasome Delivery Promotes Tau Degradation through the Ubiquitin-Proteasome System

2013년 8월 29일 16시 44분 19초
BIO.P-587 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
10월 16일 (수요일) 16:00~19:00
저자 및
한동훈, 김현영, 이민재*
경희대학교 응용화학과, Korea
The mesoporous silica nanoparticle (MSN) has been utilized as an effective drug delivery carrier, which may have potential to bring therapeutic benefits. Here, we report the first cellular delivery of 26S proteasomes (≥3MDa) conjugated with MSN and consequently enhanced proteasome activity which facilitate proteotoxic protein degradation. The surface of MSN was chemically engineered to have nickel ions to tether His-tagged proteasomes. Mammalian proteasomes were affinity-purified from HEK293-pre1-HTBH (tandem His-TEV-Biotin-His tags) cells using streptavidin. BET and BJH analysis show that MSN has enough pore size to contain the proteasome, even in the modified MSN with nickel. The surface charges of proteasomes measured by the zeta potential were converted from positive to negative, indicating that the proteasome with negative charges might be incorporated into the pores of MSN. A pull-down assay showed that the amount of conjugated proteasome was gradually increased in a higher MSN-proteasome mass ratio There was virtually no cytotoxicity by proteasome-MSN complexes, and internalization of the particles was blocked by chlorpromazine. Proteasomes retained their activity after the endocytosis-mediated cellular uptake although they virtually lost the activity in low pH environments. We furthermore observed that proteasome-MSN complexes specifically targeted tau proteins overexpressed in cultured cell models, without detrimental nonspecific proteolysis. Our results show that not only the modified MSN can serve as an effective carrier for cellular proteasome delivery, but it might provide an effective strategy to reduce the level of proteotoxic proteins in cells, which potentially has therapeutic benefits for various diseases arisen from the deficient activity of UPS.