Unravelling druggable signalling networks that control F508del-CFTR proteostasis

Hegde, Ramanath Narayana; Parashuraman, Seetharaman; Iorio, Francesco; Ciciriello, Fabiana; Capuani, Fabrizio; Carissimo, Annamaria; Carrella, Diego; Belcastro, Vincenzo; Subramanian, Advait; Bounti, Laura; Persico, Maria; Carlile, Graeme W.; Galietta, Luis J. V.; Thomas, David Y.; Bernardo, Diego di; Luini, Alberto

doi:10.7554/elife.10365

Cited by 25 publications

(24 citation statements)

References 83 publications

(127 reference statements)

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“…In addition, we sought to suppress MAP3K11, the upstream activator of both p38 and JNK, to evaluate whether this treatment improved ATP7B H1069Q recovery from the ER. MAP3K11 has been reported to effectively correct Δ508‐CFTR . Indeed, depletion of MAP3K11 resulted in strong reduction of ATP7B H1069Q in the ER (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…MAP3K11 has been reported to effectively correct D508-CFTR. (19) Indeed, depletion of MAP3K11 resulted in strong reduction of ATP7B H1069Q in the ER (Fig. 3B,C).…”

Section: Suppression Of P38 and Jnk Rescues Appropriate Localization mentioning

confidence: 86%

“…This indicates that p38‐dependent and JNK‐dependent machineries have a certain level of specificity and that inhibiting them does not seem to threaten the global quality‐control processes at the level of the ER. On the other hand, p38 and JNK inhibitors also rescue some, but not all, ER‐retained mutants of other membrane proteins, such as CFTR and P‐glycoprotein . Therefore, these p38 and JNK inhibitors might modulate specific mechanisms involved in the recognition of common (or similar) protein‐folding defects.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, p38 and JNK inhibitors also rescue some, but not all, ER-retained mutants of other membrane proteins, such as CFTR and P-glycoprotein. (19) Therefore, these p38 and JNK inhibitors might modulate specific mechanisms involved in the recognition of common (or similar) protein-folding defects.…”

Section: Discussionmentioning

confidence: 99%

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Identification of p38 MAPK and JNK as new targets for correction of Wilson disease‐causing ATP7B mutants

et al. 2016

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Wilson disease (WD) is an autosomal recessive disorder that is caused by the toxic accumulation of copper (Cu) in the liver. The ATP7B gene, which is mutated in WD, encodes a multitransmembrane domain adenosine triphosphatase that traffics from the trans‐Golgi network to the canalicular area of hepatocytes, where it facilitates excretion of excess Cu into the bile. Several ATP7B mutations, including H1069Q and R778L that are two of the most frequent variants, result in protein products, which, although still functional, remain in the endoplasmic reticulum. Thus, they fail to reach Cu excretion sites, resulting in the toxic buildup of Cu in the liver of WD patients. Therefore, correcting the location of these mutants by leading them to the appropriate functional sites in the cell should restore Cu excretion and would be beneficial to help large cohorts of WD patients. However, molecular targets for correction of endoplasmic reticulum‐retained ATP7B mutants remain elusive. Here, we show that expression of the most frequent ATP7B mutant, H1069Q, activates p38 and c‐Jun N‐terminal kinase signaling pathways, which favor the rapid degradation of the mutant. Suppression of these pathways with RNA interference or specific chemical inhibitors results in the substantial rescue of ATP7BH1069Q (as well as that of several other WD‐causing mutants) from the endoplasmic reticulum to the trans‐Golgi network compartment, in recovery of its Cu‐dependent trafficking, and in reduction of intracellular Cu levels. Conclusion: Our findings indicate p38 and c‐Jun N‐terminal kinase as intriguing targets for correction of WD‐causing mutants and, hence, as potential candidates, which could be evaluated for the development of novel therapeutic strategies to combat WD. (Hepatology 2016;63:1842‐1859)

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Section: Resultsmentioning

confidence: 99%

“…MAP3K11 has been reported to effectively correct D508-CFTR. (19) Indeed, depletion of MAP3K11 resulted in strong reduction of ATP7B H1069Q in the ER (Fig. 3B,C).…”

Section: Suppression Of P38 and Jnk Rescues Appropriate Localization mentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of p38 MAPK and JNK as new targets for correction of Wilson disease‐causing ATP7B mutants

et al. 2016

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“…Recent ΔF508-CFTR interactome and CFTR correction-related transcriptome analysis identified several E3 ligases (TRIM21, UBR4, RNF215, UBOX5, ASB8, FBXO7, SYVN1 and FBXO2) that could facilitate the ERAD in CF bronchial epithelia (Hegde et al, 2015; Pankow et al, 2015; Ramachandran et al, 2016). rΔF508-CFTR is also ubiquitinated by the peripheral QC (Fu et al, 2015; Okiyoneda et al, 2011; Okiyoneda et al, 2010; Sharma et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Chaperone-Independent Peripheral Quality Control of CFTR by RFFL E3 Ligase

et al. 2018

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The peripheral protein quality control (QC) system removes non-native membrane proteins, including ΔF508-CFTR, the most common CFTR mutant in cystic fibrosis (CF), from the plasma membrane (PM) for lysosomal degradation by ubiquitination. It remains unclear how unfolded membrane proteins are recognized and targeted for ubiquitination and how they are removed from the apical PM. Using comprehensive siRNA screens, we identified RFFL, an E3 ubiquitin (Ub) ligase that directly and selectively recognizes unfolded ΔF508-CFTR through its disordered regions. RFFL retrieves the unfolded CFTR from the PM for lysosomal degradation by chaperone-independent K63-linked poly-ubiquitination. RFFL ablation enhanced the functional expression of cell-surface ΔF508-CFTR in the presence of folding corrector molecules, and this effect was further improved by inhibiting the Hsc70-dependent ubiquitination machinery. We propose that multiple peripheral QC mechanisms evolved to dispose of non-native PM proteins and to preserve cellular proteostasis, even at the cost of eliminating partially functional polypeptides.

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Translating in vitro CFTR rescue into small molecule correctors for cystic fibrosis using the Library of Integrated Network‐based Cellular Signatures drug discovery platform

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Ramachandran

Boudko

et al. 2021

CPT Pharmacom & Syst Pharma

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Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The common ΔF508‐CFTR mutation results in protein misfolding and proteasomal degradation. If ΔF508‐CFTR trafficks to the cell surface, its anion channel function may be partially restored. Several in vitro strategies can partially correct ΔF508‐CFTR trafficking and function, including low‐temperature, small molecules, overexpression of miR‐138, or knockdown of SIN3A. The challenge remains to translate such interventions into therapies and to understand their mechanisms. One approach for connecting such interventions to small molecule therapies that has previously succeeded for CF and other diseases is via mRNA expression profiling and iterative searches of small molecules with similar expression signatures. Here, we query the Library of Integrated Network‐based Cellular Signatures using transcriptomic signatures from previously generated CF expression data, including RNAi‐ and low temperature‐based rescue signatures. This LINCS in silico screen prioritized 135 small molecules that mimicked our rescue interventions based on their genomewide transcriptional perturbations. Functional screens of these small molecules identified eight compounds that partially restored ΔF508‐CFTR function, as assessed by cAMP‐activated chloride conductance. Of these, XL147 rescued ΔF508‐CFTR function in primary CF airway epithelia, while also showing cooperativity when administered with C18. Improved CF corrector therapies are needed and this integrative drug prioritization approach offers a novel method to both identify small molecules that may rescue ΔF508‐CFTR function and identify gene networks underlying such rescue.

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Unravelling druggable signalling networks that control F508del-CFTR proteostasis

Cited by 25 publications

References 83 publications

Identification of p38 MAPK and JNK as new targets for correction of Wilson disease‐causing ATP7B mutants

Identification of p38 MAPK and JNK as new targets for correction of Wilson disease‐causing ATP7B mutants

Chaperone-Independent Peripheral Quality Control of CFTR by RFFL E3 Ligase

Translating in vitro CFTR rescue into small molecule correctors for cystic fibrosis using the Library of Integrated Network‐based Cellular Signatures drug discovery platform

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