Proteasome as a Molecular Target of Microcystin-LR.

Zhu Zhu,Li Zhang,Guoqing Shi

doi:10.3390/toxins7062221

Abstract

Proteasome degrades proteins in eukaryotic cells. As such, the proteasome is crucial in cell cycle and function. This study proved that microcystin-LR (MC-LR), which is a toxic by-product of algal bloom, can target cellular proteasome and selectively inhibit proteasome trypsin-like (TL) activity. MC-LR at 1 nM can inhibit up to 54% of the purified 20S proteasome TL activity and 43% of the proteasome TL activity in the liver of the cyprinid rare minnow (Gobiocypris rarus). Protein degradation was retarded in GFP-CL1-transfected PC-3 cells because MC-LR inhibited the proteasome TL activity. Docking studies indicated that MC-LR blocked the active site of the proteasome β2 subunit; thus, the proteasome TL activity was inhibited. In conclusion, MC-LR can target proteasome, selectively inhibit proteasome TL activity, and retard protein degradation. This study may be used as a reference of future research on the toxic mechanism of MC-LR.

Highlights

The frequent occurrence of harmful algal bloom with exacerbating inland water eutrophication has become a global environmental problem [1]
We investigated the inhibitory effects of MC-LR on the proteasome CT, post-glutamyl peptide hydrolase-like (PGPH) and TL activities of the purified 20S proteasome
The results showed that 34% of the proteasome TL activity was inhibited by MC-LR; by contrast, the proteasome PGPH activity was slightly inhibited by MC-LR, and the proteasome CT activity did not change compared with those of the control group (Figure 2b)

Summary

Introduction

The frequent occurrence of harmful algal bloom with exacerbating inland water eutrophication has become a global environmental problem [1]. MC-LR with the variable amino acids leucine (L) and arginine (R) is the most frequently investigated MC variant; MC-LR is, one of the most potent hepatotxins [6]. Well-documented toxic mechanisms for MC-LR are its inhibition to serine/threonine protein phosphatases (PPs) and induce oxidative stress in animal cells [13]. Several enzymes, such as catalase [14], glutathione S-transferase [15], L-3-hydroxyacyl coenzyme A dehydrogenase [15], aldehyde dehydrogenase 2 [16], and ATP-synthase [17], were proved to interact with MC-LR and contribute to its toxicity or biotransformation

Methods

Results

Conclusion