The CSL proteins, versatile transcription factors and context dependent corepressors of the notch signaling pathway

Abstract

The Notch signaling pathway is a reiteratively used cell to cell communication pathway that triggers pleiotropic effects. The correct regulation of the pathway permits the efficient regulation of genes involved in cell fate decision throughout development. This activity relies notably on the CSL proteins, (an acronym for CBF-1/RBPJ-κ in Homo sapiens/Mus musculus respectively, Suppressor of Hairless in Drosophila melanogaster, Lag-1 in Caenorhabditis elegans) which is the unique transcription factor and DNA binding protein involved in this pathway. The CSL proteins have the capacity to recruit activation or repression complexes according to the cellular context. The aim of this review is to describe the different co-repressor proteins that interact directly with CSL proteins to form repression complexes thereby regulating the Notch signaling pathway in animal cells to give insights into the paralogous evolution of these co-repressors in higher eumetazoans and their subsequent effects at developmental processes.

Keywords: CSL; Embryo development; Hairless; Negative regulation; Notch signaling pathway.

Fig. 1

General view of the NSP: once a ligand of the DSL family in the signal sending cell interacts with the Notch receptor of the signal receiving cell, NICD is released by proteolysis and translocated to the nucleus activating the pathway for a positive gene regulation together with CSL proteins, Mastermind (Mam) protein and histone acetyltransferases (HATs). Otherwise NSP is repressed by “default repression” complexes structured by Hairless (H) protein and C-terminal binding protein (CtBP) and Groucho (Gro) co-repressors

Fig. 2

The CSL proteins: CSL proteins are transcription factors regulating the Notch pathway in a positive and negative fashion. CSL type transcription factors have three functional domains well characterized: N-terminal domain (NTD), beta-trefoil domain (BTD) and C-terminal domain (CTD) which are used for protein–protein or protein-DNA interactions

Fig. 3

Comparative view of the repression and activation complexes. One of the best known models of the NSP is Drosophila melanogaster. CSL transcription factor acts as a bridging protein between the DNA and a complex of proteins intended to modify chromatin topology in a specific locus. In the case of the gene repression complex, CSL recruits H that in turn will form a HDAC together with Gro and CtBP. Even if H is the main co-repressor of the pathway in the fly fruit, no H homolog has been found in models out of insects, but instead a series of other proteins seem to take this function as we will see further. For the gene activation complex, NICD and Mam occupied the CSL’s domains and, in turns, recruit a HAT complex to generate an open chromatin topology and promote gene expression. Activation complexes seem to be similar in all models where NSP has been studied. Skip is common in both complexes

Fig. 4

CIR-CSL interaction: CBF-1 interacting region for CIR is located at the BTD of CBF-1 (a CSL protein) that matches the domain used by the RAM domain of NICD. This interaction suggests a competition for the transcription factor, regulating in a negative fashion genes regulated by NSP in a specific cell context

Fig. 5

MINT-CSL. The SHARP/MINT proteins were reported to function as negative regulators in diverse cellular contexts as members of a general transcription regulation machinery. MINT is a potent inhibitor of the NSP that uses the BTD and CTD of CSL to form a repression complex with this transcriptional factor to modify the chromatin topology at the NSP dependent genes

Fig. 6

KyoT-CSL. The interaction of KyoT 1 and 3 proteins with the transcription factor is mapped at the central region of CSL. This interaction still proposed the exclusive and antagonistic competition between the co-activators and the co-repressor in the NSP. Concentration of the KyoT proteins seems to play also an important role in the regulation control of genes expression, which are commune characteristics of the repression complexes in this signaling context

Fig. 7

RITA-CSL. This interaction represents a different, but still important mechanism of regulation of the NSP. In this case chromatin modification is not involved, instead the complex is shuttle out of the nucleus by activity of RITA. The CSL interacting domain with RITA is mapped at the CTD