Creld2 function during unfolded protein response is essential for liver metabolism homeostasis

Abstract

27The unfolded protein response (UPR) is associated with the hepatic metabolic function, 28 yet it is not well understood how endoplasmic reticulum (ER) disturbance might 29 influence metabolic homeostasis. Here, we describe the physiological function of 30Cysteine-rich with EGF-like domains 2 (Creld2), previously characterized as a 31 downstream target of the ER-stress signal transducer Atf6. Creld2 enhances protein 32 folding and degradation through its interaction with proteins involved in UPR, thereby, 33 promoting tolerance of chronic stress and recovery from acute stress. Creld2-34 deficiency leads to a dysregulated UPR, and causes the development of hepatic 35 steatosis in male mice, while females are protected. We observed this sex dimorphism 36 also in humans with fatty liver disease, with only males showing an accumulation of 37 CRELD2 protein in the liver. These results reveal a Creld2 function at the intersection 38 between UPR and metabolic homeostasis and suggest a mechanism in which chronic 39 ER stress underlies fatty liver disease in males. 40 41 marker for kidney disease in urine 5 and for prosthetic joint infections in synovial fluid 53 6 . However, the physiological role of Creld2 in vivo remains unknown. 54Several in vitro studies have identified Creld2 as an ER-stress inducible gene, 55 whose expression is regulated by activating transcription factor 6 (Atf6) 7,8 . ER stress 56 is characterized by an accumulation of proteins in the ER lumen. Consequently, cells 57 activate an unfolded protein response (UPR), a signaling network that collectively aims 58 at decreasing ER protein load by broad inhibition of protein synthesis and at the same 59 time promotes the activation and production of proteins that increase protein folding 60 capacity and degradation. The latter include chaperones, shuttling proteins that 61 promote secretion of proteins out of the ER and ER-associated protein degradation 62 (ERAD) components 9 . 63The UPR is controlled by three sensors: Atf6, inositol requiring enzyme 1 (Ire1), 64 and protein kinase RNA-activated (PKR)-like ER kinase (Perk). The ER luminal 65 domains of the ER stress sensors are bound and thereby inactivated by the chaperone 66Grp78 (glucose-regulated protein 78, also known as heat shock protein A5 (Hspa5)). 67Upon ER stress Grp78 is sequestered by the accumulation of proteins in the ER lumen, 68 causing the activation of the three sensors. Perk dimerizes and is activated by trans-69 autophosphorylation of its kinase domains, leading to translational inhibition through 70 eIF2a phosphorylation. This directly enhances the translation of DNA-damage-71 inducible 34 (Gadd34) and CAAT/enhancer-binding protein (C/EBP) homologous 72 protein (Chop). While Gadd34 serves as a feedback loop to dephosphorylate eIF2α 73 allowing the cell to recover from translational inhibition, increased Chop expression 74 may trigger cell death due to unresolved ER stress. The kinase Ire1 undergoes 75 autophosphorylation resulting in splicing of the X-box binding protein 1 (sXbp1) ...