Tubulin inhibitors stimulate peroxisomal import: A new perspective for primary hyperoxaluria treatment

The peroxisomal function depends entirely on protein import. The import of newly synthesized proteins is mediated by the cytosolic receptor PEX5. PEX14 docks PEX5-cargo complex and translocate it across the peroxisomal membrane. Tubulin is the major PEX14-associated protein. Moreover, tubulin and PEX5 compete for the PEX14 binding site. Thus, inhibition of PEX14-tubulin complex formation may accelerate peroxisomal import of proteins. However, this property of tubulin inhibitors has not been yet discovered.

Human alanine-glyoxylate aminotransferase (AGT), normally localized within the peroxisomes, plays an important role in glyoxylate detoxification. Absence of this enzyme causes primary hyperoxaluria type 1 (PH1) manifesting as oxalate over-production. Few AGT variants, prevalent among PH1 patients, are associated with its aberrant localization within the mitochondria. Thus, stimulation peroxisomal transport is a critical step towards conservative treatment of PH1 patients.

We developed a highly specific quantitative method for measuring peroxisomal protein import based on the split GFP approach. Using this readout in HTS screening, we identified colchicine and other tubulin inhibitors capable of prominently restoring the peroxisomal localization of an AGT mutant.

The most encouraging point is that there is no need to develop new medications, but rather to repurpose one of the most ancient known drugs. Colchicine, a plant alkaloid from autumn crocus, has been used as early as 1500 BC to treat joint swelling and currently is widely applied in medicine. Its positive effect on peroxisomal import may become useful for hyperoxaluria treatment and eventually, in other peroxisomal transport disorders.