ATF6 is essential for human cone photoreceptor development

Abstract

Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.

ATF6α contributes to rheumatoid arthritis by inducing inflammatory cytokine production and apoptosis resistance

“…ATF6α or ATF6β single knock-out mice develop normally whereas mice deficient in both ATF6 subtypes exhibit embryonic lethality ( 15 , 16 ). Upon ER stress, the N-terminal fragment of ATF6, designated pATF6(N), is cleaved from the parent protein, designated pATF6(P), and is transported into the nucleus, where it binds to the cis-acting ER stress response element (ERSE) and UPR element (UPRE) and increases the expression of genes such as GRP78/BiP, GRP94, protein disulphide isomerase (PDI), the C/EBP homologous protein (CHOP), and XBP1 ( 17 , 18 ). Although ATF6 is thought to be involved in pro-survival signaling during ER stress, its overexpression can drive the apoptotic pathway ( 19 ).…”

Imbalanced Unfolded Protein Response Signaling Contributes to 1-Deoxysphingolipid Retinal Toxicity

“…(32) As we observed, pharmacologic ATF6 activation can rescue this deficiency and restore cone photoreceptors in iPSC models of this disease. (60) Alternatively, deficiencies in ATF6 activation induced by environmental insults or aging contribute to retinal degeneration associated with other diseases including retinitis pigmentosa and cone-rod dystrophy. (34, 61) The protection afforded by ATF6 in the retina is likely mediated through its regulation of multiple adaptive genes including the ER chaperones BiP and the neurotrophic factor MANF.…”

A possible connection between reactive oxygen species and the unfolded protein response in lens development: From insight to foresight

“…Patients suffering from this disease will gradually lose cone function followed by loss of rod function ( Skorczyk-Werner et al, 2017 ). By using patient-specific iPSCs and retinal organoids, a recent study also showed that ATF6 is essential for the formation of human cone photoreceptors ( Kroeger et al, 2021 ). All the evidence confirmed the important character of ATF6 during retinal development.…”