LUMAN/CREB3 Plays a Dual Role in Stress Responses as a Cofactor of the Glucocorticoid Receptor and a Regulator of Secretion

Abstract

LUMAN/CREB3, originally identified through its interaction with a cell cycle regulator HCFC1, is a transcription factor involved in the unfolded protein response during endoplasmic reticulum stress. Previously using gene knockout mouse models, we have shown that LUMAN modulates the glucocorticoid (GC) response leading to enhanced glucocorticoid receptor (GR) activity and lower circulating GC levels. Consequently, the stress response is dysregulated, leading to a blunted stress response in the Luman-deficient mice. One question that remained was how LUMAN deficiency affected the stress response at the cellular level leading to the changes in the physiological stress response. Here, we found that LUMAN interacts with GR through a putative nuclear receptor box site and can activate GR in the absence of a ligand. Further investigation showed that, when activated, LUMAN binds to the glucocorticoid response element (GRE), increasing the activity of GR exponentially compared to GR-ligand binding alone. On the other hand, we also found that in the absence of LUMAN, cells were more sensitive to cellular stress, exhibiting decreased secretory capacity. Hence our current data suggest that LUMAN may function both as a transcriptional cofactor of GR and a hormone secretion regulator, and through this, plays a role in stress sensitivity and reactivity to stress.

CREB3 Transcription Factors: ER-Golgi Stress Transducers as Hubs for Cellular Homeostasis

“…Most of these processes require the adaptation of the secretory pathway which is regulated by CREB3 family members in multiple cell types (Fox and Andrew, 2015). In line with this, CREB3 regulates expression of genes encoding COPII components and formation of Golgi outposts in hippocampal cells (Chung et al, 2017; Penney et al, 2018).…”

“…As we mentioned above, CREB3 transcription factors can also modulate cell survival by activating expression of anti-apoptotic factors (Sheng et al, 2010). Also, CREB3 and CREB3L1 contribute to neuroendocrine regulation of the hypothalamic/pituitary/adrenal axis modulating the GR activity and the AVP gene transcription (Greenwood et al, 2014; Penney et al, 2018). Most of these processes require the adaptation of the secretory pathway which is regulated by CREB3 family members in multiple cell types (Fox and Andrew, 2015).…”

“…CREB3 knock-out mouse model (Penney et al, 2018) used to study the hypothalamic pituitary adrenal (HPA) axis and the glucocorticoid (GC) response linked CREB3 function in CNS to the secretory pathway. These animals have low levels of corticosterone and high levels of the glucocorticoid receptor (GR).…”

The minor allele of the CREBRF rs373863828 p.R457Q coding variant is associated with reduced levels of myostatin in males: Implications for body composition

“…Moreover, reduced myostatin expression has been associated with increased muscle mass in other mammals [34] To date two main roles have been identified for CREBRF; the first is to bind to the transcription factor CREB3 and regulate CREB3 levels and activity [6]. The transcription factor component CREB3 is cleaved and thus activated by ER/Golgi stress [35] and in turn plays a key role in regulating endoplasmic and Golgi stress responses in cells [36,37]. CREBRF has also been shown to regulate the cellular location and activity of the glucocorticoid receptor [38].…”

Axotomy Induces Phasic Alterations in Luman/CREB3 Expression and Nuclear Localization in Injured and Contralateral Uninjured Sensory Neurons: Correlation With Intrinsic Axon Growth Capacity

“…Thus, it is plausible to consider glucocorticoids as a potential contributor to either bilateral, contralateral, or systemic sensory nerve injury changes but the response of the HPA in the injured state needs to be characterized. Interestingly, Luman has recently been identified as a key regulator of glucocorticoid-mediated stress responses through its ability to modulate GR expression and activity (70) by binding to the GR (71). Whether this factors into the response to peripheral nerve injury remains to be determined.…”