Circadian Clocks and UPR: New Twists as the Story Unfolds

Abstract

Circadian clocks help control the unfolded protein response (UPR). In a recent issue of Nature Cell Biology, Bu et al. (2017) show that the interaction is reciprocal, with miRNA-211 providing a signal from the UPR to the clock component BMAL1, affecting circadian timing, global translational control, and cancer cell survival.

Ageing and Low-Level Chronic Inflammation: The Role of the Biological Clock

“…The intricate interplay between the circadian pathway and the UPR is operated by several components among which the microRNA miR-211 is crucial. ER stress impedes the transcription of core clock and clock-controlled genes via an ATF4-dependent mechanism [ 115 , 116 , 117 ].…”

Type I interferons and endoplasmic reticulum stress in health and disease

“…Webster et al Abbreviations: 2-DE, 2-deoxyglucose; ATF4/6, activating transcription factor 4 or 6; ATG9, autophagy related 9; BMDC, bone marrow derived dendritic cells; BMDM, bone marrow derived macrophages; CBP, cAMP response element binding protein (CREB)-binding protein; CHOP, CCAAT-enhancer-binding protein homologous protein; CK1α, casein kinase 1-alpha; DCs, dendritic cells; ER, endoplasmic reticulum; FFAs, free fatty acids; GADD34, growth-arrest and DNA damage-inducible protein 34; HCV, hepatitis C virus; IFN, interferon; IFNAR, interferon alpha/beta receptor; IRE1α, inositol-requiring enzyme 1 alpha; IRF3, interferon regulatory factor 3; ISR, integrated stress response; JAK, janus kinase; LPS, lipopolysaccharide; MDA5, melanoma differentiation-associated protein 5; mDCs, monocyte-derived dendritic cells; PBMCs, peripheral blood mononuclear cells; pDCs, plasmacytoid dendritic cells; PERK, PKR-like endoplasmic reticulum kinase; Phospho-eIF2α, phosphorylated eukaryotic translation initiation factor 2A; PKR, protein kinase R; Poly(I:C), polyinosinic:polycytidylic acid; PRR, pattern recognition receptor; RLR, retinoic acid-inducible gene I (RIG-I)-like receptors; SARS-CoV, severe acute respiratory syndrome-related coronavirus; SKIV2L, superkiller viralicidic activity 2-like RNA helicase; STAT, signal transducer and activator of transcription; STING, stimulator of interferon genes; TGEV, transmissible gastroenteritis virus; TLR, toll-like receptor; UPR, unfolded protein response; VSV, vesicular stomatitis virus; WNV, West Nile virus; XBP1, X-box binding protein 1; XBP1s, spliced XBP1 isoform; XRN1, 5 0 -3 0 exoribonuclease 1. also seems to support type I IFNs production, however this occurs much less often when compared to the IRE1/XBP1 arm (Table 1). Nonetheless in line with the complex nature of UPR's functional effects (Hazari et al, 2016;Milev and Gatfield, 2018), UPR signaling also plays a detrimental role by suppressing type I IFN responses. Based on our survey (Table 1), two main type I IFN impeding pathways emerged: (1) in most cases, UPR was found to disrupt the sensing of type I IFNs by reducing the overall expression of its cognate receptor IFNAR1; (2) in other cases, ER stress-autophagy interplay (Klionsky et al, 2016) was found to target particular components of the type I IFNs signaling pathway, thereby disrupting either the type I IFNs production itself or its IFNAR1-dependent sensing.…”

“…In couple of instances, phosphorylation of eIF2α (either by PERK or PKR) also seems to support type I IFNs production, however this occurs much less often when compared to the IRE1/XBP1 arm (Table 1). Nonetheless in line with the complex nature of UPR's functional effects (Hazari et al, 2016;Milev and Gatfield, 2018), UPR signaling also plays a detrimental role by suppressing type I IFN responses. Based on our survey (Table 1), two main type I IFN impeding pathways emerged: (1) in most cases, UPR was found to disrupt the sensing of type I IFNs by reducing the overall expression of its cognate receptor IFNAR1; (2) in other cases, ER stress-autophagy interplay (Klionsky et al, 2016) was found to target particular components of the type I IFNs signaling pathway, thereby disrupting either the type I IFNs production itself or its IFNAR1-dependent sensing.…”

The regulation of animal behavior by cellular stress responses

“…This controls the coordination of physiology according to daily cycles, regulating the sleep/wake cycle as well as other aspects of metabolism and behavior that oscillate with daily environmental changes. The circadian clock regulates UPR ER activation, with downstream effects on metabolism [ [48] , [49] , [50] ]. In turn, UPR ER regulators including PERK, ATF4 and Xbp1 can themselves regulate aspects of circadian oscillations [ [51] , [52] , [53] ].…”