Abstract
Translation is a basic cellular process and its capacity is adapted to cell function. In particular, secretory cells achieve high protein synthesis levels without triggering the protein stress response. It is unknown how and when translation capacity is increased during differentiation. Here, we show that the transcription factor Creb3l2 is a scaling factor for translation capacity in pituitary secretory cells and that it directly binds ~75% of regulatory and effector genes for translation. In parallel with this cell-autonomous mechanism, implementation of the physiological UPR pathway prevents triggering the protein stress response. Knockout mice for Tpit, a pituitary differentiation factor, show that Creb3l2 expression and its downstream regulatory network are dependent on Tpit. Further, Creb3l2 acts by direct targeting of translation effector genes in parallel with signaling pathways that otherwise regulate protein synthesis. Expression of Creb3l2 may be a useful means to enhance production of therapeutic proteins.
Highlights
Translation is a basic cellular process and its capacity is adapted to cell function
As marked upregulation of POMC expression is the hallmark of POMC cell postnatal maturation, we first assessed if this process is dependent on differentiation and/or POMC itself
Tpit-deficient pituitaries show a dramatic reduction of intermediate lobe (IL) size (Fig. 1a, b), suggesting there are either fewer cells or decreased cell size
Summary
Translation is a basic cellular process and its capacity is adapted to cell function. We show that the transcription factor Creb3l2 is a scaling factor for translation capacity in pituitary secretory cells and that it directly binds ~75% of regulatory and effector genes for translation In parallel with this cell-autonomous mechanism, implementation of the physiological UPR pathway prevents triggering the protein stress response. To identify mechanisms of POMC cell adaptation to the heavy biosynthetic burden happening at the fetal-to-adult transition, we use POMCdeficient models to show Tpit-dependent control of translation and secretory capacity through activation of two bZIP TFs, Creb3l2 and XBP1. These TFs exert their cell-autonomous action through direct targeting of genes implicated in translation and ER biogenesis, respectively
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