Xbp1-Independent Ire1 Signaling Is Required for Photoreceptor Differentiation and Rhabdomere Morphogenesis in Drosophila

Abstract

SUMMARY The Unfolded Protein Response (UPR) is composed by homeostatic signaling pathways that are activated by excessive protein misfolding in the endoplasmic reticulum (ER). Ire1 signaling is an important mediator of the UPR, leading to the activation of the transcription factor Xbp1. Here, we show that Drosophila Ire1 mutant photoreceptors have defects in the delivery of Rhodopsin-1 to the rhabdomere and in the secretion of Spacemaker/Eyes shut into the inter-rhabdomeral space. However, these defects are not observed in Xbp1 mutant photoreceptors. Ire1 mutant retinas have higher mRNA levels for targets of regulated Ire1-dependent decay (RIDD), including for the fatty acid transport protein (fatp). Importantly, downregulation of fatp by RNA interference rescues the Rhodopsin-1 delivery defects observed in Ire1 mutant photoreceptors. Our results show that the role of Ire1 during photoreceptor differentiation is independent of Xbp1 function and demonstrate the physiological relevance of the RIDD mechanism in this specific paradigm.

UPR, autophagy, and mitochondria crosstalk underlies the ER stress response

“…Of note, some of these pathways can also be activated by other stress pathways independent of bona fide UPR components, including phosphorylation of eIF2α (by GCN2, PKR, or HRI) [60]. Also, non-canonical PERK and IRE signaling has been reported [61, 62]. Tissue- or cell type-dependent expression of UPR sensors also likely mediates specialized, lineage-dependent responses [63].…”

Endoplasmic reticulum stress and the unfolded protein responses in retinal degeneration

“…Deletion of XBP1 increases IRE1 expression and activation, resulting in RIDD-mediated cleavage of cytochrome P450-encoding mRNA in the liver and the cleavage of the mRNA of secretory μ chains of IgM in plasma cells (Benhamron et al, 2013), suggesting a reciprocal regulation between XBP1 and RIDD. Interestingly, a recent study using a Drosophila model shows that RIDD is required for photoreceptor differentiation and rhabdomere morphogenesis and this effect is XBP1-independent (Coelho et al, 2013). Future studies on the function and potential implications of RIDD in retinal neuronal development and protection are consequently of great interest.…”

A new RIDDle in DC-mediated cross-presentation

“…Evidence in vivo that RIDD is an important component of the physio logical UPR or contributes to chronic UPR-driven disease processes is lacking. However, IRE-1-mediated cleavage of individual mRNAs has been shown to have functional consequences under certain dietary conditions in mice or during development in Drosophila 8,9 .…”