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. 2015 Nov 23;3(2):e1120382. doi: 10.1080/21690731.2015.1120382

Working hard at the nexus between cell signaling and the ribosomal machinery: An insight into the roles of RACK1 in translational regulation

Simone Gallo 1,*, Nicola Manfrini 1,*
PMCID: PMC4721502  PMID: 26824030

Abstract

RACK1 is a ribosome-associated protein which functions as a receptor for activated PKCs. It also acts as a scaffold for many other proteins involved in diverse signaling pathways, e.g. Src, JNK, PDE4D and FAK signaling. With such a broad interactome, RACK1 has been suggested to function as a linker between cell signaling and the translation machinery. Accordingly, RACK1 modulates translation at different levels in several model organisms. For instance, it regulates ribosome stalling and mRNA quality control in yeasts and promotes translation efficiency downstream of specific cellular stimuli in mammals. However, the molecular mechanism by which RACK1 exerts these roles is widely uncharacterized. Moreover, the full list of ribosome–recruited RACK1 interactors still needs characterization.

Here we discuss in vivo and in vitro findings to better delineate the roles of RACK1 in regulating ribosome function and translation.

Keywords: Asc1, Cpc2, eIF6, mouse, PKC, RACK1, ribosome, translation, yeast

Abbreviations

Asc1

Absence of growth Suppressor of Cyp1

Cpc2

Cross Pathway Control 2

eIF6

eukaryotic Initiation Factor 6

mTOR

mechanistic Target Of Rapamycin

PKC

Protein Kinase C

PMA

Phorbol 12-Myristate 13-Acetate

RACK1

Receptor for Activated C Kinase.

Introduction

RACK1: a 40S-associated PKC receptor which regulates 80S ribosome formation

RACK1 (Receptor for Activated C Kinase 1) is a highly conserved protein with homology to the β subunit of G proteins. It is a member of the WD40 repeat protein family, as its aminoacid sequence contains 7 Trp-Asp (WD40) domains which are important for protein-protein interactions.

RACK1 is a scaffold protein known to co-purify directly with the 40S ribosomal subunit.1,2 Cryo-EM studies on the 80S ribosome showed that RACK1 localizes on the head region of the 40S, immediately neighboring the mRNA exit channel, in contact with the surface of interaction of the eIF3 complex and right next to the Scp160 mRNA-binding protein.3,4

To date it is not known whether all ribosomes harbour RACK1. However, the persistence of its interaction with ribosomes under high-salt conditions,5 its presence being at a 1:1 ratio with other ribosomal proteins2 and its confirmed detection in eukaryotic ribosome cryo-EM maps3 indicate that under normal conditions most ribosomes in a cell do contain RACK1.

Originally, RACK1 was characterized for its interaction with activated Protein Kinase C (PKC). 6 Specifically, PKCβII, PKCδ and PKCε were all found to interact with RACK1, with PKCβII showing the highest binding affinity.7-11 Since RACK1 is a ribosome-associated protein and it binds PKC, an assessment of a physical interaction between translating ribosomes and PKC was carried out. Experimental data revealed that purified eukaryotic 80S complexes were able to phosphorylate a specific PKC substrate, MARCKS (Myristoylated Alanine-Rich C-Kinase Substrate), indicating that PKC is actually associated with the 80S ribosome.12 This evidence suggests that PKC might be able to regulate protein synthesis, a fact that was indeed confirmed by pharmacological PKC stimulation which led to a significant increase in the global rate of translation.13

This said, it was also shown that this PKC-mediated translation induction is independent of mTOR and requires RACK1,14 further strengthening the importance of the RACK1-PKC interaction and pointing out a role for RACK1 in translational control (Fig. 1).

Figure 1.

Figure 1.

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RACK1 impact on translation. (A), in vitro and in vivo evidence from yeast, human and plant indicates a role for RACK1 in promoting 80S complex formation (Shor et al., 2003; Ceci et al., 2003; Guo et al., 2011), possibly by inducing eIF6 release from the 60S subunit; (B), in S. cerevisae cells the RACK1 ortholog needs to bind to the 40S subunit in order to stall the ribosome when translating non-stop mRNAs (Kuroha et al., 2010; Chiabudini et al., 2014; Matsuda et al., 2014; Wolf and Greyhack, 2015); (C), in human cells, RACK1 recruits JNK and eEF1A2 on the ribosome to mediate proteasome-dependent degradation of misfolded newly synthetized polypeptides (Gandin et al., 2013); (D), in human cells, RACK1 docks specific RNPs (mRNAs complexed with mRNA-binding proteins) on the ribosome and promotes mRNA translation in a Src-dependent manner (Ceci et al., 2012); (E), in mice, RACK1 activates translation downstream of insulin and PKC stimulation (Volta, Beugnet et al., 2012).

Importantly, RACK1 was shown to interact with eIF6 (eukaryotic Initiation Factors 6) in vitro. eIF6 is a translation initiation factor that is required for ribosome biogenesis and which localizes on the 60S ribosomal subunit.15 eIF6 binding site on the 60S has been mapped to the 40S-60S interface, where it prevents by steric hindrance the formation of the most important bonds between the 2 subunits.16 Indeed, when eIF6 is bound to the 60S subunit, 80S complex formation is impaired.15,17

Accordingly, eIF6 over-expression was shown to cause a translational block and impairment of 80S ribosome formation.15 Strikingly, in mammalian cells such effects are reversed by stimulating PKC in vitro or by over-expressing RACK1, indicating that PKC and RACK1 may act synergistically to promote 80S complex formation.15 Consistently, experiments performed on the plant model Arabidopsis thaliana showed an impairment of 80S ribosome formation upon RACK1 downregulation (Fig. 1A).18 Indeed, PKC stimulation leads to eIF6 phosphorylation and the RACK1/PKC-mediated translational rescue described above is impaired in cells overexpressing an eIF6 variant in which Ser235 is substituted by a non-phosphorylatable residue.15 On these basis, it has been proposed that upon translation initiation the RACK1/PKC complex phosphorylates eIF6 on residue Ser235, thus permitting its dissociation from the 60S subunit and allowing formation of the 80S ribosome. 15,19 This model establishes a clear functional link between RACK1 and translation initiation (Fig. 1A), although it is still not clear how RACK1 at the solvent side of the 40S subunit is able to regulate eIF6 on the 60S. To overcome this apparent issue and explain 80S formation, we can propose that 40S-bound RACK1 can promote eIF6 release from different 60S subunits which would then be free to associate with other 40S subunits (themselves able to promote eIF6 release from other 60S subunits). Such a scenario would favor fast and coordinated formation of multiple 80S complexes locally available for efficient translation.

Besides docking PKC, RACK1 has been found to interact with an increasing variety of proteins and to be involved in a number of signaling pathways that may play direct or indirect roles in translation regulation. Indeed, RACK1 is proposed to act as a physical link between the ribosome and the signal transduction machineries in order to allow modulation of translation in response to different types of cellular stimuli.

Although these observations suggest a functional role for RACK1 in translation, they also raise several questions. In particular: i) does RACK1 have other roles in regulating translation besides mediating eIF6 release from the 60S ribosomal subunit and inducing 80S complex formation? ii) besides PKCs, could any other interactor of RACK1 have a role in translation? iii) is RACK1 able to specifically modulate translation downstream of cellular signaling?

In this review we will try to address, at least in part, these long-standing questions. We will at first discuss results obtained from unicellular eukaryotic models, we will then analyze experiments carried out in human cells in vitro and conclude with data from murine models.

RACK1 Yeast Orthologs Control Specific mRNA Translation and Transcript Quality

RACK1 is a protein well conserved throughout evolution, therefore simple model organisms such as yeasts are a suitable tool to study RACK1 functions.cpc2, the ortholog of RACK1 in Schizosaccharomyces pombe, is not essential. However, cpc2Δ yeast cells show decreased translation levels and fewer polysomes, effects that may account for impaired ribosomal joining and deficient 80S ribosome formation (Fig. 1A). Other than affecting translation on a quantitative level, Cpc2 is proposed to be involved in regulating the translation of specific mRNA subtypes. In particular, in cpc2Δ cells, the polysomal recruitment of the mRNA encoding for ribosomal protein rpL25 is partially impaired, accounting for reduced translation efficiency of the rpL25 transcript.20

In line with this evidence, Cpc2 binding to the ribosome is required to increase the level of proteins involved in different cellular processes, such as the activation of the MAPK cascade, the response against oxidative stress and cell cycle progression.21 This indicates that Cpc2-dependent translational regulation of specific mRNAs requires Cpc2 localization on the ribosome.

Consistently with the data for Schizosaccharomyces pombe Cpc2, also Saccharomyces cerevisiae RACK1 ortholog ASC1 is suggested to be important to modulate specific mRNA translation. In particular the Asc1-regulated transcripts encode for proteins involved in various cellular processes, e.g. mitochondrial biogenesis, glycolysis, response to oxidative stress and maintenance of cell wall integrity.22

Moreover, Asc1 was also shown to be involved in ribosome stalling. It is well established that translation of mRNAs without a stop codon causes the ribosome to stall on the mRNA and translation to be halted. In this context, ASC1 deletion causes lack of ribosome stalling. Such phenotype is suppressed by expressing wild-type ASC1 but not an asc1 mutant allele with reduced affinity for the ribosome, indicating that Asc1 needs to bind to the ribosome in order to trigger its stalling.23 In addition, Asc1 is important to prevent frameshifts during translation of mRNAs containing CGA codon repeats,24 further implying a role for Asc1 in translation quality control (Fig. 1B).

Such role in the quality control of translating mRNAs was expanded by a recent work which directly implicated Asc1 in the degradation of aberrant mRNAs through non-canonical and still unknown mechanisms. 25 Consistently, Asc1-mediated translational arrest is also required for the degradation of the nascent polypeptides being synthesized from the aberrant mRNAs. In particular, the E3-ubiquitin ligase Ltn1 mediates the degradation of such polypeptides and its function is lost upon ASC1 deletion,26 pointing out an important role for RACK1/Asc1 in regulating the stability not only of aberrant mRNAs but also of their derived polypeptides (Fig. 1B).

These observations underline the impact of RACK1/Cpc2/Asc1 on different aspects of translational machinery regulation. Indeed, RACK1 orthologs in yeast not only can regulate 80S complex formation, but are also able to specifically control both the efficiency and quality of mRNA translation.

Jnk, Src and Other Proteins Interact With RACK1 to Modulate Translation

It is known that RACK1 can interact with different types of protein domains, but their full range still needs to be determined. Among all, SH2 (Src Homology 2) domains27 and PH (Pleckstrin Homology) domains28,29 have been identified as possible RACK1 interaction candidates, suggesting a concrete involvement of RACK1 in signaling pathways regulated by completely different molecular mechanisms, e.g. tyrosine phosphorylation and phosphoinositide binding.

Accordingly, beside PKCs, a huge and heterogeneous number of other in vitro RACK1 interactors has been reported, ranging from cytosolic kinases and phosphatases, to virus proteins and membrane-bound receptors. A selection of literature-reported RACK1 interactors is summarized in Table 1. More in detail, confirmed interactors include kinases such as the c-Jun N-terminal Kinase (JNK)30,31 and Src,32,33 neuronal membrane-bound receptors such as the N-Methyl-D-Aspartate (NMDA) receptor and the β subunit of the GABAA receptor,34,35 RNA-binding proteins,36 adhesion molecules such as β1-integrins11,37 and enzymes such as PDE4D5.38

Table 1.

Selected RACK1 protein interactors. A list of interactors from literature are reported with references in chronological order.

RACK1 interactor Function Organism Reference
PKCβ Signaling Frog, Rat 8,9
c-Src Signaling Human 27
β1-integrin Cell adhesion Human 11,49
GABA (Gamma-Amino Butyric Acid) receptor type A Synaptic inhibition Rat 35
Interleukin 3, Interleukin 5, GM-CSF (Granulocyte Macrophage Colony-Stimulating Factor) receptors Signaling Human 50
PDE4D (cAMP-specific Phosphodiesterase) isoform 5 cAMP levels modulation Mouse, Monkey, Human 38,51,52
Interferon receptor type 1 Antiviral, antiproliferative, immunomodulatory Human 53
M1 (Influenza A virus ) Regulatory function Bird Swine, Human 54
Adenovirus E1A protein Viral infection and replication Yeast, Human 55
PKCδ, PKCμ Signaling Human 10
IGF-1R (Insulin-like Growth Factor 1 Receptor) Cell survival, proliferation and differentiation regulation Mouse, Human 10,56
NMDA (N-methyl D-Aspartate) receptor Synaptic plasticity Mouse 34
Plectin Regulation of actin dynamics/cytoskeletal linker Human 57
JNK (Jun-N-terminal kinase) Stress response Human 30
HIF-1α (Hypoxia Inducible Factor 1α), Elongin C-E3 ubiquitin ligase O2-independent degradation of HIF-1α Human 58
FAK (Focal Adhesion Kinase) Mediation of integrin signaling Mouse, Human 56
H3, H4 histones BDNF transcription activation Human 59
BMAL1 (Brain and Muscle Arnt-like protein 1) Circadian rhythms regulation Mouse 60
14-3-3ζ-14-3-3θ Signaling Human 61
ZBP1 (Z-DNA-binding protein 1) Recruitment of β-actin mRNA on the ribosome Human 40
FBW2 (F-box and WD-repeat domain-containing 2) Prevention of ubiquitin-mediated degradation of transcription factor GCM Human 62
Vimentin Endothelial cell invasion Human 63
eEF1A2 (eukaryotic Elongation Factor 1 α isoform 2) Stress-induced degradation of newly synthetized polypeptides Human 39
Keratin Cell structure Mouse 64
SERRATE Accumulation and processing of some pri-miRNA Plant 65
AGAP2 (ArfGAP With GTPase Domain, Ankyrin Repeat And PH Domain 2) FAK regulation and focal adhesion assembly Rat 66
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Taking a look at interactions with possible feedback on translation, recent data identified a RACK1/JNK/eEF1A2 complex in which 40S-bound RACK1 recruits on the ribosome the stress-induced JNK protein. JNK then phosphorylates the eukaryotic translation Elongation Factor 1 α isoform 2 (eEF1A2) in order to promote degradation of the newly synthesized polypeptides by the proteasome.39 This mechanism links RACK1 once again to polypeptide degradation, but what is more also to translation elongation (Fig. 1C). Interestingly, these observations from human cells confirm a role for RACK1 in monitoring translation quality, albeit not through the same mechanism observed in yeast.23-26

RACK1 is also reported to be required for the docking on the ribosome of specific Ribonucleic Particles (RNPs), e.g., β-actin mRNA in complex with RNA-binding protein ZBP1. The phosphorylation by Src of both RACK1 and ZBP1 is shown to be important for the recruitment of RNPs to RACK1 and for the release of ZBP1 from the mRNA, in turn allowing translation.40 This provides important evidence that Src, a protein not known to be directly involved in translation regulation, can synergize with RACK1 on the ribosome to promote the translation of specific mRNAs (Fig. 1D).

As mentioned, among the many published interactors of RACK1 there are several proteins possessing prominent roles in cell adhesion (e.g. β1-integrin, FAK and plectin). Accordingly, it has been proposed that RACK1 may not only recruit signaling molecules to the ribosome, but also regulate ribosome recruitment to specific sub cellular compartments.3 This would possibly contribute to deliver the translational machinery to cellular locations where rapid and efficient in loco protein synthesis is required. For instance RACK1 seems to be involved in the regulation of adhesion-stimulated translation (e.g., induced by the presence of fibronectin as an extracellular substrate for adhering and spreading cells). Supporting this hypothesis, cells which are spreading and migrating were shown to accumulate ribosomes and translation factors at the sites of adhesion complexes enriched for integrins.41 This and other evidence suggesting a role for RACK1 in coupling migration with protein synthesis were previously thoroughly discussed in a review by Gandin and collegues to which we refer the reader to.42 This said, to date there is no definitive proof indicating that RACK1 is able to physically connect the adhesion and ribosome machineries leaving the field open and worthy of future investigation.

To summarize, multiple proteins require RACK1 to affect translation. However, since a more comprehensive annotation of RACK1 interactome is needed, we are currently lacking the data required to define the precise molecular mechanism(s) through which RACK1 regulates translation.

RACK1 is Fundamental for Insulin- and PMA-Regulated Translation

Characterization of a murine model mutated for RACK1 demonstrated that homozygosity for a RACK1 hypomorphic allele is lethal during the gastrulation phase of embryogenesis.43 Notably, depletion of essential ribosomal proteins results in embryogenesis being halted before implantation, suggesting that RACK1 is dispensable for ribosomal integrity and for overall translation in mice.

Furthermore, mice heterozygous for a RACK1 hypomorphic allele are viable and show a pigmentation deficit, featuring a white belly spot, a depigmented tail and hindfoot pads.43 Interestingly, this phenotype is shared with that of the Bst (Belly spot and tail) mouse model, which is heterozygous for the ribosomal protein rpL24.44 This suggests that the phenotype of hypomorphic RACK1 heterozygous mice might be due to a role of RACK1 in regulating ribosomal function.

The mild phenotype of hypomorphic RACK1 heterozygous mice as well as the phenotypes of several other mouse models mutated in ribosomal proteins can be rescued by p53 inactivation.45 In these contexts p53 is activated downstream of ribosomal stress, with an imbalance between ribosomal proteins being the signal for impaired ribosome biogenesis.46 Given that, in a p53-/- background, hypomorphic RACK1 homozygous mice remain not viable, we can assert that the lethality caused by lack of RACK1 during embryogenesis is independent of ribosomal stress-mediated activation of p53.43 This suggests that RACK1 is not essential for ribosomal integrity and favors on speculating that its fundamental function is linked to specific translation regulation.

Indeed, it was observed that, while the basal translation efficiency of RACK1 heterozygous MEFs (Murine Embryonic Fibroblasts) is normal, such cells are unable to increase their translation rate in response to insulin or PKC stimulation via PMA (Phorbol 12-myristate 13-acetate).43 These findings demonstrate that RACK1 is directly involved in regulating translation in response to insulin and PMA treatment (Fig. 1E). Strikingly, this phenomena phenocopies what was observed in eIF6 heterozygous MEFs,19 further supporting the existence of a functional link between RACK1 and eIF6.

To conclude, in mammals RACK1 is able to regulate translation downstream of specific stimuli i.e. growth factors and insulin signaling. Therefore, it is possible that RACK1 can affect protein synthesis at a qualitative level. This is in concordance with the evidence from yeast which indicates that RACK1 orthologs can affect the translation of specific mRNA subtypes.20,21

Concluding remarks

RACK1 is a protein involved in an increasing amount of cellular functions, among which translation regulation plays a prominent role. In multiple model organisms, RACK1 is shown to regulate translation by specifically promoting 80S ribosome formation. However, given the complexity of the RACK1 interactome and its involvement in multiple signaling pathways it is not surprising that RACK1 can also affect translation in other ways.

Data from yeast and mammals shows that RACK1 expression is not fundamental for ribosomal integrity and overall translation. Nonetheless, in mice, RACK1 is required for modulating protein synthesis in response to several cellular stimuli.

In different model organisms, ranging from yeasts to human cells, RACK1 is also shown to modulate translation of specific mRNAs.20,21,40 This is further supported by experimental evidence from Drosophila melanogaster which indicates that RACK1 is involved in regulating the translation of specifically structured mRNAs, i.e., mRNAs containing IRES (Internal Ribosome Entry Site) elements.47

Still, the evidence of RACK1 being able to influence the translation rate (and possibly to contribute to the selection of the mRNAs to be translated) is at odds with its position on the ribosome, being it on the 40S subunit on the opposite side of the mRNA entry site. It is thus difficult to propose a molecular mechanism by which RACK1 could directly recruit and/or regulate mRNA translation by localizing on the ribosome. However, indirect mechanisms could be mediated through RACK1 interactors. For example, the interaction between RACK1 and eIF3 has been proposed to stabilize the 43S pre-initiation complex.48 So far, however, it is left unclear how such interactions could lead to the regulation of specific mRNA translation.

For what we said so far, we can conclude that RACK1 may regulate protein synthesis both quantitatively and qualitatively. Unluckily, the precise physiological significance of RACK1-dependent translation is still unestablished since the translatome of cells depleted for RACK1 has yet to be fully characterized.

Future studies are needed to depict a more exhaustive view of RACK1 functions in translation. Of particular relevance would be the investigation of important topics like: i) which are the mRNA regulatory sequences and structures that require RACK1 for modulating translation? ii) what are the molecular basis by which specific mRNAs can be translationally regulated by RACK1? iii) which of RACK1-dependent signaling pathways require a physical link with the ribosome and/or are relavant in translation? Answering these and other open questions will lead to a greater understanding of how RACK1 operates in connecting the translation machinery with cellular signaling pathways.

Disclosure of Potential Conflict of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We wish to thank Professor Stefano Biffo for his advice and for critical reading of the manuscript.

Funding

We thank the European Research Council (ERC) for funding.

References

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