Table 2 |.
RBP–effector interactions in human disease
| RBP–effector interaction | Genetic disorder or developmental abnormality | Causative or associated mutation | Therapeutic approach |
|---|---|---|---|
|
| |||
| Disease-linked mutations that affect RBP–effector interactions | |||
|
| |||
| FUS–TNPO1 | ALS, rare cases of FTLD143 | Mutations in PY-NLS or | NR |
| HNRNPA1–TNPO1 | ALS175 | cNLS of RBPs | |
| HNRNPH2–TNPO1 | Neurodevelopmental delay, autism148 | ||
| TDP43–Kapβ1/Impα | ALS176,177 | ||
|
| |||
| MATR3–TREX complex | ALS, vocal cord and pharyngeal weakness with distal myopathy149,178 | Mutations in IDRs of MATR3 | NR |
|
| |||
| RBP–SMN | SMA48,179 | Mutations in the Tudor domain of SMN | NR |
|
| |||
| Therapeutically targeted RBP–effector interactions | |||
|
| |||
| SRSF6–U1 snRNP | Familial dysautonomia (Riley–Day syndrome) | Intronic mutation in ELP1 | Small-molecule CLK1 agonist-enhanced SRSF6 phosphorylation to rescue abnormal skipping of the IKBKAP exon 20 (ref.156) |
|
| |||
| SRSFs–U1/U2 snRNPs | Duchenne muscular dystrophy, cystic fibrosis, anhidrotic ectodermal dysplasia with immunodeficiency | Exonic mutation in DMD, intronic mutations in CFTR and IKBKG | Pharmacological CLK inhibition to suppress SRSF phosphorylation and pathogenic exon inclusion158,180,181 |
|
| |||
| SRSFs–U1 snRNP | Leukaemia, prostate cancer, colon cancer, breast cancer, lung cancer, neovascular eye disease | Cancer-associated mutations in tumour suppressor genes and oncogenes | Inhibition of SRPK activity to normalize isoform levels of genes linked to cancer progression, apoptosis and angiogenesis159–162 |
|
| |||
| FUS–TNPO1 EWSR1–TNPO1 TAF15–TNPO1 HNRNPA1–TNPO1 HNRNPA2–TNPO1 TDP43–Kapβ1/Impα |
ALS, FTLD, Alzheimer disease, multisystem proteinopathy | Aggregation-promoting mutations in RBPs or disrupted arginine methylation | Delivery of NIRs to afflicted neurons or modulation of arginine methyltransferase activity52–55,127,164 |
|
| |||
| ATXN2–PABPC | Spinocerebellar ataxia 2, ALS | Expansion of the polyglutamine domain in ATXN2 | Designer PABPC-like chaperones to counter pathogenic RNP condensate formation85 |
|
| |||
| ZFP36–CCR4–NOT | Rheumatoid arthritis, psoriasis, multiple sclerosis, juvenile idiopathic arthritis, inflammatory diseases | Mutations in and/or reduced expression of ZFP36, aberrant signalling | PP2A agonists to activate ZFP36 or forced expression of ZFP36 in peripheral tissues or immune cells165,166,182,183 |
|
| |||
| RBM38–eIF4E | Cancers | NR | SLiM-mimicking synthetic peptide Pep8 increases expression of p53 by blocking the inhibitory RBM38-eIF4E interaction169 |
ALS, amyotrophic Lateral sclerosis; ATXN2, ataxin 2; cNLS, lysine-rich NLS; FTLD, frontotemporal lobar degeneration; MATR3, matrin 3; NIR, nuclear import receptor; NLS, nuclear localization sequence; NR, not reported; PABPC, cytoplasmic poly(A)-binding protein; PP2A, protein phosphatase 2A; PY-NLS, proline-tyrosine-rich NLS; RBP, RNA-binding protein; SLiM, short linear motif; SMA, spinal muscular atrophy; SMN, survival motor neuron protein; snRNP, small nuclear ribonucleoprotein; TNPO1, transportin 1; TREX, transport and export.