CELFish ways to modulate mRNA decay

Abstract

The CELF family of RNA-binding proteins regulates many steps of mRNA metabolism. Although their best characterized function is in pre-mRNA splice site choice, CELF family members are also powerful modulators of mRNA decay. In this review we focus on the different modes of regulation that CELF proteins employ to mediate mRNA decay by binding to GU-rich elements. After starting with an overview of the importance of CELF proteins during development and disease pathogenesis, we then review the mRNA networks and cellular pathways these proteins regulate and the mechanisms by which they influence mRNA decay. Finally, we discuss how CELF protein activity is modulated during development and in response to cellular signals. We conclude by highlighting the priorities for new experiments in this field. This article is part of a Special Issue entitled: RNA Decay mechanisms.

Fig 1

CELF protein domain structure and conservation. Each human CELF protein is depicted with the level of identity to CELF1 denoted by the color of blue shading for each RR, the linker region and the C-terminal nuclear localization signal (NLS). Darker shading indicates more homology. Other motifs including Q-rich domains, oligomerization domain, the conserved N-terminal extension of RRM3 and a nuclear export signal (NES) found in CELF2 (as defined in [16]) are also shown. Regions of RRM3 affected by alternative splicing in CELF2 and CELF4 are indicated. ELAVL1 is shown for comparison, but has less than 50% identity in all domains. Protein sequences used for this alignment were CELF1 Isoform 1 (NP_006551.1), CELF2 Isoform 1 (NP_001020247.1), CELF3 Isoform 1 (NP_009116.3), CELF4 Isoform 1 (NP_064565.1), CELF5 Isoform 1 (NP_068757.2), CELF6 Isoform 2 (NP_001166155.1), ELAVL1 (NP_001410.2).

Fig. 2

Comparison of AU-Rich and GU-Rich Elements. Functions and factors unique to each type of element are depicted with shared properties shown in the darker overlapping region. Over-represented biological processes were identified using Ingenuity Pathway Analysis (Ingenuity Systems, Inc.).

Fig. 3

CELF proteins recruit deadenylases through direct or indirect interaction with the mRNA 5′ cap structure. (A) PARN is recruited directly to its substrates through interaction with CELF1. PARN activity is stimulated by the 5′ cap. (B) Bruno interacts indirectly with the 5′ cap through the eIF4E binding protein, Cup. Cup can recruit the CCR4/NOT deadenylase to mRNAs.

Fig. 4

Post-translational modifications of CELF1 and CELF2 proteins. Experimentally verified phosphorylation and acetylation sites and the likely enzymes responsible are shown. In addition, serine-rich regions within the linker domain are depicted as they represent possible sites for phosphorylation by kinases such as PKC.

Fig. 5

CELF1 relocalizes to cytoplasmic granules upon heat shock in mouse myoblasts. C2C12 cells were incubated at 37°C (left) or 44 °C for 2 hours prior to fixing and staining for CELF1 using 3B1 monoclonal antibody (Santa Cruz Biotechnology Inc.) and Cy2 conjugated goat anti-mouse secondary antibody (Jackson ImmunoResearch). These images are intended to illustrate CELF1 relocalization as reported by others following heat shock in HeLa cells [91].