Biology subjects

Sitia, R.

Publications and source records attributed to Sitia, R..

3 recordsLinked to original sources

bioRxiv2025

Unveiling novel signaling roles for human KDELR3 and KDELR1KDELRs Control AGR2 Biogenesis

KDEL receptors (KDELRs) prevent the secretion of soluble chaperones and enzymes meant to reside in the endoplasmic reticulum. While a single KDELR exists in yeast (ERD2), three variants are present in mammals, displaying high sequence similarity (73-83%). However, the phylogenetic conservation of the differences and the diverse tissue distribution of the three KDELRs suggest functional specialization. Here we show that, while all three receptors can prevent the secretion of KDEL-bearing clients, KDELR1 and KDELR3 regulate the production of AGR2, a key assistant of mucin folding, in opposite ways. AGR2 transcripts increase dramatically upon silencing KDELR3 but decrease when KDELR1 is downregulated. Silencing ERp44, but not other ER residents, phenocopies KDELR3 knockdown, suggesting that AGR2 regulation depends on ERp44-KDELR3 interactions. Our findings identify a novel regulatory circuit that controls the molecular composition of the early secretory pathway based on specific interactions between KDELRs and ER residents.

cell biology↗

bioRxiv2023

Congress of multiple dimers is needed for cross-phosphorylation of IRE1α and its RNase activity

The unfolded protein response can switch from a pro-survival to a maladaptive, pro-apoptotic mode. During endoplasmic reticulum (ER) stress, IRE1 sensors dimerize, are phosphorylated and activate XBP1 splicing, increasing folding capacity in the ER protein factory. The steps that turn the IRE1 endonuclease activity against endogenous mRNAs during maladaptive ER stress are still unknown. Here we show that although necessary, IRE1 dimerization is not sufficient to trigger phosphorylation. Random and/or guided collisions amongst IRE1 dimers are needed to elicit cross-phosphorylation and endonuclease activities. Thus, reaching a critical concentration of IRE1 dimers in the ER membrane is a key event. Formation of stable IRE1 clusters is not necessary for RNase activity. However, clustering could modulate the potency of the response promoting interactions between dimers and decreasing the accessibility of phosphorylated IRE1 to phosphatases. The stepwise activation of IRE1 molecules and their low concentration at steady state prevent excessive responses, unleashing full-blown IRE1 activity only upon intense stress conditions.

cell biology↗

bioRxiv2017

The unfolded protein response turns from pro-survival to pro-death to cap the extent of endoplasmic reticulum expansion

Insufficient folding capacity of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to restore homeostasis. Yet, how the UPR achieves and evaluates ER homeostatic readjustment is poorly understood. In a HeLa cell model we show that, upon a severe proteostatic insult that eclipses the ER chaperone BiP, the UPR transitions from acute full-gear activation to chronic submaximal activation, when BiP is in excess again. As such, the UPR-driven ER expansion is pro-survival, primarily via the UPR transducer ATF6. Simultaneous abrogation of ER-associated degradation (ERAD) leads to chronic full-gear UPR activation and further ER expansion, but the UPR transducers IRE1 and PERK turn pro-apoptotic. Pro-survival XBP1 mRNA processing by IRE1 is then trumped since unspliced XBP1 mRNA is depleted and IRE1s endonuclease activity is unleashed against other RNAs. Thus, the IRE1/XBP1 relay serves as a capacitor of ER expansion that heralds cell death if the expansion is deemed excessive.

cell biology↗