Regulation of basal cellular physiology by the homeostatic unfolded protein response

Abstract

The extensive membrane network of the endoplasmic reticulum (ER) is physically juxtaposed to and functionally entwined with essentially all other cellular compartments. Therefore, the ER must sense diverse and constantly changing physiological inputs so it can adjust its numerous functions to maintain cellular homeostasis. A growing body of new work suggests that the unfolded protein response (UPR), traditionally charged with signaling protein misfolding stress from the ER, has been co-opted for the maintenance of basal cellular homeostasis. Thus, the UPR can be activated, and its output modulated, by signals far outside the realm of protein misfolding. These findings are revealing that the UPR causally contributes to disease not just by its role in protein folding but also through its broad influence on cellular physiology.

Figure 1.

Evolutionary expansion of the UPR allows for regulatory modulation and variable inputs and outputs. The evolutionarily conserved IRE1 arm of the UPR (green) has been expanded in metazoans by the parallel PERK and ATF6 pathways (blue). Each of these stress transducers is sensitive to protein misfolding stress in the ER, and they collectively contribute to gene regulation and UPR output. Each transducer can also interact with additional factors (orange) shared with signaling pathways responsive to other stimuli. These accessory interactions can thereby modulate the canonical stress response output contingent on cellular conditions. Physiological stimuli can further shape UPR outputs by differentially acting on the UPR at both proximal and distal steps. Two illustrative examples are depicted using red and black dashed lines. In the first example, TLR engagement activates all three UPR transducers, while simultaneously suppressing ATF4 production (Woo et al., 2009). TLR-stimulated UPR-independent pathways operate in parallel, such that TLR stimulation influences and is influenced by UPR activation to determine the final output. The second example illustrates plasma cell differentiation, where a differentiation stimulus initiates a differentiation program that includes selective activation of the ATF6-α and IRE1-α pathways of the UPR. The UPR pathways increase ER protein processing capacity, thereby facilitating the high level of antibody production and secretion that accompanies differentiation (Gass et al., 2008; Ma et al., 2010). The selectivity of UPR activation in this case precludes PERK-mediated responses, which might act at cross-purposes to differentiation.

Figure 2.

Potential activation mechanisms for the UPR during physiological stimulation. (A) Global protein misfolding stress in the ER results in activation of all three UPR sensors. ER chaperones (blue) can maintain UPR signal transducers in an inactive state during quiescent conditions. Unfolded proteins can activate the stress transducers by indirect chaperone titration or direct transducer binding. The global balance between chaperone reserve and ER folding clients might represent the stimulus for physiological activation of the UPR, with parallel signaling pathways modifying the activity and/or abundance of phosphatases, proteases, nucleases, etc. that determine net UPR output. However, it is likely that at least some physiological stimuli are capable of activating UPR pathways selectively by several hypothetical mechanisms. (B) First, a UPR sensor could be preferentially sensitive to the folding status of certain types of substrates or specific environmental conditions (e.g., redox status; left). Second, spatial restriction of UPR transducers and/or individual substrates might lead to localized preferential activation (middle). And third, stimulated dimerization of IRE1-α or PERK in trans (or enforced ectopic transit of ATF6-α to the Golgi, where it is activated) could activate limbs of the UPR independently of the ER folding status. These or other hypothetical mechanisms might be used during different physiological stimuli, and they need not be mutually exclusive.

Figure 3.

UPR-mediated feedback inhibition of insulin signaling. Nutritional intake upon feeding stimulates insulin release, which initiates at least two signaling pathways in the liver (green) that impact the ER in distinct ways. First, enhanced protein synthesis caused by mTOR activation increases general substrate load in the ER. Second, activation of SREBP pathways stimulate production of lipoproteins such as VLDL, whose components are assembled in the ER. These (and possibly other) effects activate the UPR, which can inhibit insulin action by multiple feedback mechanisms (orange). Although this feedback inhibition likely serves a beneficial role during the postprandial state, it could become deleterious during chronic overnutrition. IR, insulin receptor; IRS, IR substrate.