Abstract
The aminoguanidine compound robenidine is widely used as an antibiotic for the control of coccidiosis, a protozoal infection in poultry and rabbits. Interestingly, robenidine is structurally similar to guanabenz (analogs), which are currently undergoing clinical trials as cytoprotective agents for the management of neurodegenerative diseases. Here we show that robenidine and guanabenz protect cells from a tunicamycin-induced unfolded protein response to a similar degree. Both compounds also reduced the tumor necrosis factor α-induced activation of NF-κB. The cytoprotective effects of guanabenz (analogs) have been explained previously by their ability to maintain eIF2α phosphorylation by allosterically inhibiting protein phosphatase PP1:PPP1R15A. However, using a novel split-luciferase-based protein-protein interaction assay, we demonstrate here that neither robenidine nor guanabenz disrupt the interaction between PPP1R15A and either PP1 or eIF2α in intact cells. Moreover, both drugs also inhibited the unfolded protein response in cells that expressed a nonphosphorylatable mutant (S51A) of eIF2α. Our results identify robenidine as a PP1:PPP1R15A-independent cytoprotective compound that holds potential for the management of protein misfolding-associated diseases.
Highlights
The aminoguanidine compound robenidine is widely used as an antibiotic for the control of coccidiosis, a protozoal infection in poultry and rabbits
The unfolded protein response (UPR) and integrated stress response (ISR) are both regulated by a negative feedback loop that involves the delayed expression of PPP1R15A, known as growth arrest and DNA damage–induced protein 34 (GADD34) or R15A, which forms a trimeric complex with protein phosphatase 1 (PP1) and G-actin [5, 6]
Robenidine reduced the antiproliferative effects of tunicamycin (Fig. 2), dampened TNF␣-induced NF-B activation (Fig. 3), and inhibited the expression of ISR and UPR markers (Fig. 5)
Summary
The antibiotic robenidine exhibits guanabenz-like cytoprotective properties by a mechanism independent of protein phosphatase PP1:PPP1R15A. Using a novel split-luciferase– based protein–protein interaction assay, we demonstrate here that neither robenidine nor guanabenz disrupt the interaction between PPP1R15A and either PP1 or eIF2␣ in intact cells Both drugs inhibited the unfolded protein response in cells that expressed a nonphosphorylatable mutant (S51A) of eIF2␣. The third sensor is protein kinase R–like endoplasmic reticulum kinase, which phosphorylates the ␣ subunit of eIF2␣ at Ser-51 to reduce global translation while enhancing the translation of specific stress response genes such as ATF4, CHOP, and PPP1R15A [4]. The latter branch of the UPR is part of the more general integrated stress response (ISR) pathway. Our data identify robenidine as a novel aminoguanidine with therapeutic potential for the treatment of protein misfolding diseases
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