The effects of IRE1, ATF6, and PERK signaling on adRP-linked rhodopsins

Area of Science:

• Cell Biology
• Genetics
• Ophthalmology

Background:

• Mutations in the rhodopsin gene are a primary cause of retinitis pigmentosa (RP), leading to photoreceptor cell death.
• Misfolded rhodopsin accumulates in rod photoreceptor cells, triggering cell death and vision loss in RP patients.
• The unfolded protein response (UPR) pathways, including IRE1, ATF6, and PERK, are critical for maintaining endoplasmic reticulum function and protein folding.

Purpose of the Study:

• To investigate the effects of selectively activating IRE1, ATF6, and PERK signaling pathways on misfolded rhodopsin.
• To determine if these UPR pathways can prevent rhodopsin misfolding or promote the clearance of misfolded rhodopsin.
• To explore potential therapeutic strategies for RP by targeting UPR pathways.

Main Methods:

• Utilized chemical and genetic methods to selectively activate IRE1, ATF6, or PERK signaling pathways individually.
• Analyzed the impact of pathway activation on both wild-type and mutant rhodopsin levels in cellular models.
• Quantified the degradation and aggregation of rhodopsin in response to UPR pathway modulation.

Main Results:

• Selective activation of IRE1 and ATF6 signaling pathways promoted the degradation of mutant rhodopsin, with minimal impact on wild-type rhodopsin.
• IRE1 and ATF6 signaling significantly reduced the levels of aggregated rhodopsins.
• PERK signaling reduced both wild-type and mutant rhodopsin levels, indicating less specific clearance.

Conclusions:

• Activation of IRE1, ATF6, or PERK signaling pathways can prevent the accumulation of mutant rhodopsin in cells.
• Targeted activation of IRE1 or ATF6 selectively clears aggregated and mutant rhodopsin, presenting a promising therapeutic avenue for RP.
• These findings highlight the potential of modulating UPR pathways for treating retinitis pigmentosa associated with rhodopsin misfolding.