<i>Myh10</i>deficiency leads to defective extracellular matrix remodeling and pulmonary disease

Kim, Hyun-Taek; Yin, Wenguang; Jin, Young-June; Panza, Paolo; Gunawan, Felix; Grohmann, Beate; Buettner, Carmen; Sokòl, Anna M.; Preussner, Jens; Guenther, Stefan; Kostin, Sawa; Ruppert, Clemens; Bhagwat, Aditya; Ma, Xuefei; Graumann, Johannes; Looso, Mario; Güenther, Andreas; Adelstein, Robert S.; Offermanns, Stefan; Stainier, Didier Y. R.

doi:10.1101/414268

Cited by 8 publications

(12 citation statements)

References 72 publications

(53 reference statements)

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“…An N-ethyl-N-nitrosourea Mutant Displays Growth Retardation and Goblet Cell Hyperplasia. To identify regulators of early postnatal lung development in mouse, we performed N-ethyl-Nnitrosourea (ENU) mutagenesis (39,40). From screening the F3 progeny of 170 G1 mice, we identified 10 families displaying recessive lung inflammation phenotypes.…”

Section: Resultsmentioning

confidence: 99%

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WNT/RYK signaling restricts goblet cell differentiation during lung development and repair

Kim

Yin

Nakamichi

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Goblet cell metaplasia and mucus hypersecretion are observed in many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the regulation of goblet cell differentiation remains unclear. Here, we identify a regulator of this process in anN-ethyl-N-nitrosourea (ENU) screen for modulators of postnatal lung development;Rykmutant mice exhibit lung inflammation, goblet cell hyperplasia, and mucus hypersecretion. RYK functions as a WNT coreceptor, and, in the developing lung, we observed high RYK expression in airway epithelial cells and moderate expression in mesenchymal cells as well as in alveolar epithelial cells. From transcriptomic analyses and follow-up studies, we found decreased WNT/β-catenin signaling activity in the mutant lung epithelium. Epithelial-specificRykdeletion causes goblet cell hyperplasia and mucus hypersecretion but not inflammation, while club cell-specificRykdeletion in adult stages leads to goblet cell hyperplasia and mucus hypersecretion during regeneration. We also found that the airway epithelium of COPD patients often displays goblet cell metaplastic foci, as well as reduced RYK expression. Altogether, our findings reveal that RYK plays important roles in maintaining the balance between airway epithelial cell populations during development and repair, and that defects in RYK expression or function may contribute to the pathogenesis of human lung diseases.

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Section: Resultsmentioning

confidence: 99%

“…For RNA sequencing (RNA-Seq), total RNA was isolated from P1 lungs of 2 Ryk +/+ and 2 Ryk SL/SL mice. Whole-exome sequencing and RNA-Seq were performed as previously described (39).…”

Section: Methodsmentioning

confidence: 99%

WNT/RYK signaling restricts goblet cell differentiation during lung development and repair

Kim

Yin

Nakamichi

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…As expected, GO biological process analysis of TNFAIP1-interacting proteins revealed that TNFAIP1 was associated with the cytoskeleton. Among the proteins enriched in these pathways, 6 proteins were involved in cytoskeleton regulation, as shown by analysis of a protein-protein interaction network including FLNB, TLN1, RACGAP1, KIF23, SNX9, and MYH10 [41][42][43][44][45][46][47] . We speculated that BTBD9 affected the expression of these proteins by modulating TNFAIP1 degradation and altering the metastatic ability of lung cancer cells.…”

Section: Discussionmentioning

confidence: 99%

The CRL3BTBD9 E3 ubiquitin ligase complex targets TNFAIP1 for degradation to suppress cancer cell migration

Zhang

Liu

et al. 2020

Sig Transduct Target Ther

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Tumor necrosis factor alpha-induced protein 1 (TNFAIP1) modulates a plethora of important biological processes, including tumorigenesis and cancer cell migration. However, the regulatory mechanism of TNFAIP1 degradation remains largely elusive. In the present study, with a label-free quantitative proteomic approach, TNFAIP1 was identified as a novel ubiquitin target of the Cullin-RING E3 ubiquitin ligase (CRL) complex. More importantly, Cul3-ROC1 (CRL3), a subfamily of CRLs, was identified to specifically interact with TNFAIP1 and promote its polyubiquitination and degradation. Mechanistically, BTBD9, a specific adaptor component of CRL3 complex, was further defined to bind and promote the ubiquitination and degradation of TNFAIP1 in cells. As such, downregulation of BTBD9 promoted lung cancer cell migration by upregulating the expression of TNFAIP1, whereas TNFAIP1 deletion abrogated this effect. Finally, bioinformatics and clinical sample analyses revealed that BTBD9 was downregulated while TNFAIP1 was overexpressed in human lung cancer, which was associated with poor overall survival of patients. Taken together, these findings reveal a previously unrecognized mechanism by which the CRL3 BTBD9 ubiquitin ligase controls TNFAIP1 degradation to regulate cancer cell migration.

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“…Two actin-binding proteins, MYH9 and MYH10, are depleted from the complexes when NSP1 is present. Interestingly, it has been reported that depletion or inactivation of the myosin non-muscle proteins MYH9 and MYH10 leads to renal failure (Otterpohl et al, 2020) or pulmonary disease (Kim et al, 2018), characteristic symptoms of SARS-CoV-2 infection.…”

Section: The Sars-cov-2 5'utr Does Not Bind To Any Component Of the Rmentioning

confidence: 99%

The viral protein NSP1 acts as a ribosome gatekeeper for shutting down host translation and fostering SARS-CoV-2 translation

Tidu

Janvier

Schaeffer

et al. 2020

RNA

120

119

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SARS-CoV-2 coronavirus is responsible for Covid-19 pandemic. In the early phase of infection, the single-strand positive RNA genome is translated into non-structural proteins (NSP). One of the first proteins produced during viral infection, NSP1, binds to the host ribosome and blocks the mRNA entry channel. This triggers translation inhibition of cellular translation. In spite of the presence of NSP1 on the ribosome, viral translation proceeds however. The molecular mechanism of the so-called viral evasion to NSP1 inhibition remains elusive. Here, we confirm that viral translation is maintained in the presence of NSP1 and we show that the evasion to NSP1-inhibition is mediated by the cis-acting RNA hairpin SL1 in the 5'UTR of SARS-CoV-2. Only the apical part of SL1 is required for viral translation. We further show that NSP1 remains bound on the ribosome during viral translation. We suggest that the interaction between NSP1 and SL1 frees the mRNA accommodation channel while maintaining NSP1 bound to the ribosome. Thus, NSP1 acts as a ribosome gatekeeper, shutting down host translation and fostering SARS-CoV-2 translation in presence of the SL1 5'UTR hairpin. SL1 is also present and necessary for translation of sub-genomic RNAs in the late phase of the infectious program. Consequently, therapeutic strategies targeting SL1 should affect viral translation at early and late stages of infection. Therefore, SL1 might be seen as a genuine 'Achille heel' of the virus.

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Myh10deficiency leads to defective extracellular matrix remodeling and pulmonary disease

Cited by 8 publications

References 72 publications

WNT/RYK signaling restricts goblet cell differentiation during lung development and repair

WNT/RYK signaling restricts goblet cell differentiation during lung development and repair

The CRL3BTBD9 E3 ubiquitin ligase complex targets TNFAIP1 for degradation to suppress cancer cell migration

The viral protein NSP1 acts as a ribosome gatekeeper for shutting down host translation and fostering SARS-CoV-2 translation

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