RT Journal Article
SR Electronic
T1 Targeted Degradation of Proteins Localized in Subcellular Compartments by Hybrid Small Molecules
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 159
OP 166
DO 10.1124/mol.116.105569
VO 91
IS 3
A1 Keiichiro Okuhira
A1 Takuji Shoda
A1 Risa Omura
A1 Nobumichi Ohoka
A1 Takayuki Hattori
A1 Norihito Shibata
A1 Yosuke Demizu
A1 Ryo Sugihara
A1 Asato Ichino
A1 Haruka Kawahara
A1 Yukihiro Itoh
A1 Minoru Ishikawa
A1 Yuichi Hashimoto
A1 Masaaki Kurihara
A1 Susumu Itoh
A1 Hiroyuki Saito
A1 Mikihiko Naito
YR 2017
UL http://molpharm.aspetjournals.org/content/91/3/159.abstract
AB Development of novel small molecules that selectively degrade pathogenic proteins would provide an important advance in targeted therapy. Recently, we have devised a series of hybrid small molecules named SNIPER (specific and nongenetic IAP-dependent protein ERaser) that induces the degradation of target proteins via the ubiquitin-proteasome system. To understand the localization of proteins that can be targeted by this protein knockdown technology, we examined whether SNIPER molecules are able to induce degradation of cellular retinoic acid binding protein II (CRABP-II) proteins localized in subcellular compartments of cells. CRABP-II is genetically fused with subcellular localization signals, and they are expressed in the cells. SNIPER(CRABP) with different IAP-ligands, SNIPER(CRABP)-4 with bestatin and SNIPER(CRABP)-11 with MV1 compound, induce the proteasomal degradation of wild-type (WT), cytosolic, nuclear, and membrane-localized CRABP-II proteins, whereas only SNIPER(CRABP)-11 displayed degradation activity toward the mitochondrial CRABP-II protein. The small interfering RNA–mediated silencing of cIAP1 expression attenuated the knockdown activity of SNIPER(CRABP) against WT and cytosolic CRABP-II proteins, indicating that cIAP1 is the E3 ligase responsible for degradation of these proteins. Against membrane-localized CRABP-II protein, cIAP1 is also a primary E3 ligase in the cells, but another E3 ligase distinct from cIAP2 and X-linked inhibitor of apoptosis protein (XIAP) could also be involved in the SNIPER(CRABP)-11–induced degradation. However, for the degradation of nuclear and mitochondrial CRABP-II proteins, E3 ligases other than cIAP1, cIAP2, and XIAP play a role in the SNIPER-mediated protein knockdown. These results indicate that SNIPER can target cytosolic, nuclear, membrane-localized, and mitochondrial proteins for degradation, but the responsible E3 ligase is different, depending on the localization of the target protein.