Deregulation of CRTCs in Aging and Age-Related Disease Risk

Abstract

Advances in public health in the last century have seen a sharp increase in human life expectancy. With these changes have come increased incidence of age-related pathologies and health burdens in the elderly. Patient age is the biggest risk factor for multiple chronic conditions that often occur simultaneously within one individual. An alternative to disease centric therapeutic approaches is that of 'geroscience', which aims to define molecular mechanisms that link age to overall disease risk. One such mechanism is deregulation of CREB-regulated transcriptional coactivators, CRTCs. Initially identified for their role in modulating CREB transcription, the last five years has seen an expansion in knowledge of new cellular regulators and roles of CRTCs beyond CREB. CRTCs have been shown to modulate organismal aging in C. elegans and to impact age-related diseases in humans. Here, we discuss CRTC deregulation as a new driver of aging, and integrating link between age and disease risk.

CRTC2 regulates plasma cell metabolism and survival

“…In lymphocytes, MYC binds thousands of genes and acts to broadly amplify the expression of bound genes rather than functioning as an on/off switch (Nie, Hu et al, 2012). By an imperfect analogy, we identified CRTC2 bound to more than 4,500 genes in naïve WT mouse B cells by ChIP-seq (unpublished observation), many of which were not predicted as CREB target genes, in agreement with prior results that showed CRTC proteins interact with additional bZIP family transcription factors (Escoubas, Silva-Garcia et al, 2017). In TG PCs, large changes in expression of specific genes were few, but small changes in expression did occur for numerous genes between TG and WT PCs.…”

“…Patients harboring mutations in ATM exhibit defective antibody responses (Staples, McDermott et al, 2008) and mouse B cells lacking LKB1 fail to generate ASCs in vitro (Walsh, Waters et al, 2015). Identifying direct CRTC2-bound genes may help elucidate potential stage-specific targets, although this may prove challenging as CRTCs bind and co-activate multiple bZIP transcription factors in addition to CREB (Escoubas et al, 2017). In addition, CRTC family member proteins may have redundant functions, making stage-specific CRTC2 deletion studies difficult to interpret.…”

Non-Canonical Activation of CREB Mediates Neuroprotection in aC. elegansModel of Excitotoxic Necrosis

“…CRTC/CRTC-1 acts downstream of SIK2/AAK-2 to regulate neuroprotection in nematode excitotoxicity AAK-2 has been previously shown to phosphorylate CRTC-1, thus determining its cytoplasmic vs. nuclear distribution (Altarejos and Montminy 2011;Mair et al 2011;Sasaki et al 2011;Burkewitz et al 2014Burkewitz et al , 2015Escoubas et al 2017). However, AAK-2 has also been shown to regulate the activity of FoxO/DAF-16 to modulate levels of neurodegeneration (Greer et al 2007;Tullet et al 2014;Vazquez-Manrique et al 2016).…”

Involvement of 5‐HT‐BDNF signaling axis in mediating synergistic antidepressant‐like effects after combined administration of two oligosaccharide esters

“…In addition, several other studies have indicated rapid enhancement of BDNF expression and synaptic plasticity in the special regions of brain, which is responsible for the antidepressant effect (Udina et al., 2016). Also, the transcription activator CREB has also been shown to be central in response to many signal cascades activated through growth factor, synaptic activity, and other cellular stimuli related to neuronal plasticity (Escoubas et al., 2017; H. Liu et al., 2015; Ning et al., 2019). Moreover, an equally important coactivator CRTC, also known as transducer of regulated CREB (TORC), has been recognized to play an important role in influencing CREB function (Heinrich et al., 2013).…”