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A cathepsin L-specific inhibitor preferentially inhibits degradation of autophagosomal LC3 and GABARAP in HeLa and Huh-7 cells

CAA0225 ((2S,3S)-oxirane-2,3-dicarboxylic acid 2-[((S)-1-benzylcarbamoyl-2-phenyl-ethyl)-amide] 3-{[2-(4-hydroxy-phenyl)-ethyl]-amide}) is a cathepsin L-specific inhibitor recently selected out by extensive screening of a series of new epoxysuccinyl peptides. CAA0225 inhibited rat liver cathepsin L with IC50 values of 1.9 nM, but not rat liver cathepsin B (IC50, >1000-5000 nM). We compared effects of CAA0225 on autophagy with those of CA-074 that was previously developed as a cathepsin B-specific inhibitor. In HeLa and Huh-7 cells cultured under nutrient-deprived conditions both CAA0225 and CA-074 significantly and comparably inhibited degradation of long-lived proteins. Meanwhile, CAA0225 effectively inhibited degradation of LC3-II and GABARAP, whereas CA-074-OMe had only a marginal effect on their levels. Therefore, cathepsin L does not seem to play a general role in the degradation of proteins in the lumen of autophagosomes, but is involved more specifically in the degradation of autophagosomal membrane markers.