Beyond the cell factory: Homeostatic regulation of and by the UPRER

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Science Advances  15 Jul 2020:
Vol. 6, no. 29, eabb9614
DOI: 10.1126/sciadv.abb9614


  • Fig. 1 The three primary branches of UPRER modulated by IRE1, PERK, and ATF6.

    There are three branches of UPRER, each consisting of a transmembrane protein with a luminal-facing sensor for damage, which then signals to the nucleus through a unique transcription factor. When IRE1 senses misfolded protein or lipid stress in the ER, it homodimerizes, is autophosphorylated, and promotes splicing of XBP1u mRNA to XBP1s which is translated into functional XBP1s, acting as a transcription factor to turn on genes important for restoring ER homeostasis. Similarly, PERK and ATF6 are activated under ER stress. When PERK is activated, it also oligomerizes, causing phosphorylation of eIF2α to inhibit global translation. There is also downstream activation of ATF4, which promotes the expression of ER-restoring genes that escape down-regulation via eIF2α. Unlike the other two ER stress sensors, ATF6 is proteolytically cleaved under ER stress, which causes translocation to the Golgi for further processing, allowing ATF6 to function as a transcription factor.

  • Fig. 2 Activation of the UPRER in neural cells promotes global changes in ER health in peripheral tissue.

    In C. elegans (left), overexpression of xbp-1s in neurons promotes two distinct changes to ER homeostasis in peripheral tissue (intestine): increased protein homeostasis by up-regulation of chaperones and increased lipid metabolism through mobilization of lipids via lipases, desaturases, and increased lipophagy. Both the increase in protein folding and decreased lipids are essential for the life-span extension found in this paradigm. Ectopic expression of xbp-1s in glia has also been shown to promote peripheral protein homeostasis and extend life span, although a role in glial signaling in lipid homeostasis has yet to be described. A similar phenomenon was also found in mice (right), where overexpression of Xbp1s in Pomc neurons (or simply activating Pomc neurons via olfactory exposure to food) is sufficient to drive UPRER in peripheral tissue. Specifically, XBP1s in POMC neurons promotes XBP1s and mTOR signaling in hepatocytes and adipose tissue, resulting in increased metabolic health, including resistance to diabetes and obesity. As UPRER has been shown to be critical in proper muscle and B cell function, it would be of great interest to investigate whether neuronal XBP1s can signal to elicit a beneficial effect in these and other cell types.

  • Fig. 3 UPRER in apoptosis and cell survival signals.

    Functionally, the UPRER serves as a quality control mechanism to restore ER form and function under conditions of stress. However, under sustained and unresolved ER stress, UPRER can actually promote cell death through apoptosis. For example, sustained PERK signaling can promote the activation of CHOP through ATF4, which activates proapoptotic signals. The other branches of UPRER can also modulate MAPK signaling, which feeds into cell survival or apoptotic cues in various ways. For example, IRE-1 can activate both prosurvival signals through activation of ERK1/2 and proapoptotic signals through JNK depending on the ER stress conditions. Beyond the UPRER, extracellular cues can promote cell survival under ER stress. Specifically, the cell surface hyaluronidase, TMEM2, cleaves high–molecular weight hyaluronic acid (HMW HA) into low–molecular weight hyaluronic acid (LMW HA), which acts as a ligand to the CD44 receptor and activates downstream p38 and ERK1/2 prosurvival signals.

  • Fig. 4 Role of UPRER in immune response.

    The immune response and the UPRER have both been shown to affect the other. Mounting an immune response requires the synthesis of many proteins, including several secreted factors, which makes a functional ER imperative during pathogenic infection. Thus, under exposure to pathogens, UPRER is activated to promote protein homeostasis. In addition, to avoid cell death, immune signals may dampen the PERK arm to inhibit apoptosis. UPRER components can also alter immunity through IRE1-mediated activation of TRAF2, which can promote cytokine signaling through NF-κB or directly alter transcription of immune response genes through p38 MAPK signaling.

  • Fig. 5 Cross communication of the UPRER and OxSR.

    It is becoming increasingly clear that cellular stress responses are not completely separate, and there exist notable cross communication and interdependent regulation. The UPRER and oxidative stress response (OxSR) have been shown to functionally affect the other, such that targets of XBP1s affect redox homeostasis and targets of NRF2 affect ER homeostasis. One study in C. elegans showed that transcriptional output of SKN-1 was, to a certain extent, dependent on XBP-1s function and vice versa. There are also some studies in mammalian systems that hint to similar signaling pathways, where NRF2 promotes ER quality control genes and XBP1s promotes genes involved in redox homeostasis. Another study found that glutathione synthesis genes (GSH) were potentially downstream of ATF6 signaling.

  • Fig. 6 The role of the IRE1/XBP1 pathway in modulating autophagy.

    The IRE1/XBP1 pathway has been shown to regulate autophagy both through direct transcriptional regulation of autophagic genes downstream of XBP1s and indirectly through other signaling molecules, including FOXO1 and JNK. IRE1 can promote JNK signaling through TRAF2-mediated pathways similar to the apoptosis machinery and thus activate BCL1/2 to promote autophagy. XBP1s can also activate autophagy either by inhibiting FOXO1 signaling, which releases its inhibitory effect on autophagy, or by promoting conversion of LC3 I to LC3 II.

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