Cytosolic glutaredoxin 1 is upregulated in AMD and controls retinal pigment epithelial cells proliferation via β-catenin

WILMS C; MENNEL S; HANSCHMANN E. M; HOLUBIEC M.I; GODOY J.R; FALK L; LILLIG C.H

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2022

0006-291X

Thioredoxin (Trx) family proteins are key players in redox signaling. Here, we have analyzed glutaredoxin (Grx) 1 and Grx2 in age-related macular degeneration (AMD) and in retinal pigment epithelial (ARPE-19) cells. We hypothesized that these redoxins regulate cellular functions and signaling circuits such as cell proliferation, Wnt signaling and VEGF release that have been correlated to the pathophysiology of AMD. ARPE-19 cells were transfected with specific siRNAs to silence the expression of Grx1 and Grx2 and were analyzed for proliferation/viability, migration capacity, b-catenin activation, and VEGF release. An active site-mutated C-X-X-S Grx1 was utilized to trap interacting proteins present in ARPE-19 cell extracts. In both, AMD retinas and in ARPE-19 cells incubated under hypoxia/reoxygenation conditions, Grx1 showed an increased nuclear localization. Grx1-silenced ARPE-19 cells showed a significantly reduced proliferation and migration rate. Our trapping approach showed that Grx1 interacts with b-catenin in a dithiol- disulfide exchange reaction. Knock-down of Grx1 led to a reduction in both total and active b-catenin levels. These findings add redox control to the regulatory mechanisms of b-catenin signaling in the retinal pigment epithelium and open the door to novel therapeutic approaches in AMD that is currentlytreated with VEGF-inhibitors