Tribbles homolog 3-mediated targeting the AKT/mTOR axis in mice with retinal degeneration

• Published in: Cell death & disease Vol. 12; no. 7; p. 664
• Main Authors: Saltykova, Irina V., Elahi, Asif, Pitale, Priyam M., Gorbatyuk, Oleg S., Athar, Mohammad, Gorbatyuk, Marina S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-07-2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/106; 13/95; 14/19; 631/337/574; 64/110; 692/699; 82/80; 96/2; 96/63; Ablation; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; AKT protein; Animals; Antibodies; Autophagosomes - genetics; Autophagosomes - metabolism; Autophagosomes - pathology; Autophagy; Autophagy-Related Protein 5 - genetics; Autophagy-Related Protein 5 - metabolism; Beclin-1 - genetics; Beclin-1 - metabolism; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Disease Models, Animal; Homeostasis; Immunology; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Phagocytosis; Phosphorylation; Photoreceptor Cells, Vertebrate - enzymology; Photoreceptor Cells, Vertebrate - pathology; Photoreceptors; Proto-Oncogene Proteins c-akt - metabolism; Retina; Retinal degeneration; Retinal Degeneration - enzymology; Retinal Degeneration - genetics; Retinal Degeneration - pathology; Rhodopsin; Rhodopsin - metabolism; Signal Transduction; Therapeutic targets; TOR protein; TOR Serine-Threonine Kinases - metabolism; Translation; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Vacuoles
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03944-w

Various retinal degenerative disorders manifest in alterations of the AKT/mTOR axis. Despite this, consensus on the therapeutic targeting of mTOR in degenerating retinas has not yet been achieved. Therefore, we investigated the role of AKT/mTOR signaling in
rd16
retinas, in which we restored the AKT/mTOR axis by genetic ablation of pseudokinase TRB3, known to inhibit phosphorylation of AKT and mTOR. First, we found that TRB3 ablation resulted in preservation of photoreceptor function in degenerating retinas. Then, we learned that the mTOR downstream cellular pathways involved in the homeostasis of photoreceptors were also reprogrammed in
rd16
TRB3
−/−
retinas. Thus, the level of inactivated translational repressor p-4E-BP1 was significantly increased in these mice along with the restoration of translational rate. Moreover, in
rd16
mice manifesting decline in p-mTOR at P15, we found elevated expression of Beclin-1 and ATG5 autophagy genes. Thus, these mice showed impaired autophagy flux measured as an increase in LC3 conversion and p62 accumulation. In addition, the RFP-EGFP-LC3 transgene expression in
rd16
retinas resulted in statistically fewer numbers of red puncta in photoreceptors, suggesting impaired late autophagic vacuoles. In contrast, TRIB3 ablation in these mice resulted in improved autophagy flux. The restoration of translation rate and the boost in autophagosome formation occurred concomitantly with an increase in total Ub and rhodopsin protein levels and the elevation of E3 ligase Parkin1. We propose that TRB3 may retard retinal degeneration and be a promising therapeutic target to treat various retinal degenerative disorders.