Regulation of transcription factor activity by interconnected post-translational modifications

Abstract

Transcription factors comprise just over 7% of the human proteome and serve as gatekeepers of cellular function, integrating external signal information into gene expression programs that reconfigure cellular physiology at the most basic levels. Surface-initiated cell signaling pathways converge on transcription factors, decorating these proteins with an array of post-translational modifications (PTMs) that are often interdependent, being linked in time, space, and combinatorial function. These PTMs orchestrate every activity of a transcription factor over its entire lifespan--from subcellular localization to protein-protein interactions, sequence-specific DNA binding, transcriptional regulatory activity, and protein stability--and play key roles in the epigenetic regulation of gene expression. The multitude of PTMs of transcription factors also offers numerous potential points of intervention for development of therapeutic agents to treat a wide spectrum of diseases. We review PTMs most commonly targeting transcription factors, focusing on recent reports of sequential and linked PTMs of individual factors.

Figure 1. Types of PTMs

Figure 2. Relative enrichment of PTMs in transcription factors

Values are the relative ratio of PTMs identified in human transcription factors compared to those identified in non-transcription factor human proteins and are plotted to show the divergence from equality for the indicated PTM. Blue bars indicate the degree of over-enrichment in transcription factors and the red bar indicates the degree of under-ubiquitination. PTM data was drawn from the PhosphoSitePlus database [1]. Abbreviations: Ub, ubiquitination; Ac, acetylation; Me, methylation; PO₄, phosphorylation; OG, O-GlcNAcylation, and SU, sumoylation.

Figure 3. Mechanisms by which PTMs may alter transcription factor activity

To alter gene expression, phosphorylation may affect the secondary structure of a transcription factor (Δ Conformation) to reveal binding sites or alter affinity, increase or decrease protein degradation (Δ Stability), increase or decrease the nuclear occupancy and thus access to DNA (Localization), alter affinity for DNA regulatory regions (DNA Binding), or alter the modification of the factor by other PTMs including acetylation, sumoylation, methylation, O-GlcNAcylation, or ubiquitination.

Figure 4. Sequential regulation of BCL11B by phosphorylation and sumoylation

BCL11B, constitutively in the context of the NuRD repressor complex (NuRD), is subject to modification by kinases, phosphatases (PPTase), sumo-ligating enzymes (UBC9), sumo proteases (SENPx), and sumo-dependent ubiquitin-targeted ligases (StUBL) that alter its activity at the Id2 oncogene promoter over a 60 min time frame following mouse thymocyte stimulation. Termination of the stimulated signal involves ubiquitin-targeted degradation by the proteasome complex.