The Role of Mammalian Creb3-Like Transcription Factors in Response to Nutrients

Abstract

Our ability to overcome the challenges behind metabolic disorders will require a detailed understanding of the regulation of responses to nutrition. The Creb3 transcription factor family appears to have a unique regulatory role that links cellular secretory capacity with development, nutritional state, infection, and other stresses. This role in regulating individual secretory capacity genes could place this family of transcription factors at an important regulatory intersection mediating an animal’s responses to nutrients and other environmental challenges. Interestingly, in both humans and mice, individuals with mutations in Creb3L3/CrebH, one of the Creb3 family members, exhibit hypertriglyceridemia (HTG) thus linking this transcription factor to lipid metabolism. We are beginning to understand how Creb3L3 and related family members are regulated and to dissect the potential redundancy and cross talk between distinct family members, thereby mediating both healthy and pathological responses to the environment. Here, we review the current knowledge on the regulation of Creb3 family transcription factor activity, their target genes, and their role in metabolic disease.

CrebA increases secretory capacity through direct transcriptional regulation of the secretory machinery, a subset of secretory cargo, and other key regulators

“…The direct regulation of the classic UPR regulator Xbp1 by CrebA is intriguing since all of the mammalian CrebA orthologs-the five members of the Creb3L protein family-were originally proposed to function in the UPR [28][29][30] and may indeed be activated in response to a number of endogenous and exogenous cellular stresses. 31 As with the other non-Creb3-like UPR TFs, the full-length Creb3L TFs are tethered to the ER through a C-terminal TM domain, and can only enter the nucleus and regulate transcription after they are released from the ER via regulated proteolytic cleavage. Studies of the UPR typically utilize drugs to induce massive protein misfolding in the ER.…”

“…37 A recent report, moreover, reveals a role for Creb3L1 in goblet cell differentiation, where defects in mucus vesicles and ER morphology occur in association with decreased mucus production. 38 The limited loss-of-function phenotypes observed with loss of individual Creb3L genes likely reflects potential redundant functions of this gene family 31 ; removal of more than one of the Creb3L genes in mammals is likely to cause more profound and widespread defects, recapitulating the strong phenotypes of the mutant Drosophila ortholog.…”

A Creb3-Like Transcription Factor Coordinates ER Function upon Food Intake to Regulate Lipid Metabolism

“…Further, mammalian Creb3L family members are able to activate expression of the same genes as CrebA targets when expressed in flies (Fox et al, 2010;Barbosa et al, 2013). In general, CrebA orthologs have roles in biological processes that require secretion, such as in bone/cartilage development and liver function (Khan and Margulies, 2019). Since we found CrebA to be nutritionally regulated in the fat body, whose roles are analogous to the mammalian liver, we targeted the function of Creb3L family members in the liver.…”

“…By monitoring changes in gene expression by genome-wide profiling of gene expression and RNA polymerase II (Pol2) function, we identified an evolutionary conserved transcription factor, CrebA, which regulates cellular secretory capacity in response to feeding. We extended our analysis to show its mammalian orthologs of the Creb3L transcription factor family (Khan and Margulies, 2019) are acutely upregulated upon refeeding to coordinate the expression of genes with roles in sorting proteins into the ER and between the ER and the Golgi. We also tested whether CrebA levels alter fly feeding behavior and the levels of circulating ApoB protein.…”

A systems based framework to computationally predict putative transcription factors and signaling pathways regulating glycan biosynthesis

“…Once the stress is detected in the endoplasmic reticulum (ER) or Golgi apparatus, their cytoplasmic domains cleave and are transported to the nucleus to act as transcription factors 21 . The CREB3L4 molecule is associated with detection of protein folding stress in the ER 22 . This molecule has been found to be upregulated in breast cancer respect to normal.…”