Dataset Information

Peptidyl-prolyl cis-trans isomerase NIMA interacting 1 regulates skeletal muscle fusion through structural modification of Smad3 in the linker region.

ABSTRACT: Myoblast fusion is critical for muscle growth, regeneration, and repair. We previously reported that the enzyme peptidyl-prolyl cis-trans isomerase NIMA interacting 1 (Pin1) is involved in osteoclast fusion. The objective of this study was to investigate the possibility that Pin1 also inhibits myoblast fusion. Here, we show the increased number of nuclei in the Pin1+/- mice muscle fiber compared to that in wild-type mice. Moreover, we show that low dose of the Pin1 inhibitor dipentamethylene thiuram monosulfide treatment caused enhanced fusion in C2C12 cells. The R-Smads are well-known mediators of muscle hypertrophy and hyperplasia as well as being substrates of Pin1. We found that Pin1 is crucial for maintaining the stability of Smad3 (homologues of the Drosophila protein, mothers against decapentaplegic (Mad) and the Caenorhabditis elegans protein Sma). Our results show that serine 204 within Smad3 is the key Pin1-binding site during inhibition of myoblast fusion and that both the transforming growth factor-? receptor and extracellular signal-regulated kinase (ERK)-mediated phosphorylation are required for the interaction of Pin1 with Smad3. These findings suggest that a precise level of Pin1 activity is essential for regulating myoblast fusion during myogenesis and muscle regeneration.

SUBMITTER: Islam R

PROVIDER: S-EPMC6686165 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Peptidyl-prolyl cis-trans isomerase NIMA interacting 1 regulates skeletal muscle fusion through structural modification of Smad3 in the linker region.

Islam Rabia R Yoon Heein H Shin Hye-Rim HR Bae Han-Sol HS Kim Bong-Soo BS Yoon Won-Joon WJ Woo Kyung-Mi KM Baek Jeong-Hwa JH Lee Yun-Sil YS Ryoo Hyun-Mo HM

Journal of cellular physiology 20180821 12

Myoblast fusion is critical for muscle growth, regeneration, and repair. We previously reported that the enzyme peptidyl-prolyl cis-trans isomerase NIMA interacting 1 (Pin1) is involved in osteoclast fusion. The objective of this study was to investigate the possibility that Pin1 also inhibits myoblast fusion. Here, we show the increased number of nuclei in the Pin1<sup>+/-</sup> mice muscle fiber compared to that in wild-type mice. Moreover, we show that low dose of the Pin1 inhibitor dipentame ...[more]

PMID: 30132832

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Project description:BACKGROUND:The peptidyl-prolyl cis/trans isomerase (PPIase) class of proteins is present in all known eukaryotes, prokaryotes, and archaea, and it is comprised of three member families that share the ability to catalyze the cis/trans isomerisation of a prolyl bond. Some fungi have been used as model systems to investigate the role of PPIases within the cell, however how representative these repertoires are of other fungi or humans has not been fully investigated. RESULTS:PPIase numbers within these fungal repertoires appears associated with genome size and orthology between repertoires was found to be low. Phylogenetic analysis showed the single-domain FKBPs to evolve prior to the multi-domain FKBPs, whereas the multi-domain cyclophilins appear to evolve throughout cyclophilin evolution. A comparison of their known functions has identified, besides a common role within protein folding, multiple roles for the cyclophilins within pre-mRNA splicing and cellular signalling, and within transcription and cell cycle regulation for the parvulins. However, no such commonality was found with the FKBPs. Twelve of the 17 human cyclophilins and both human parvulins, but only one of the 13 human FKBPs, identified orthologues within these fungi. hPar14 orthologues were restricted to the Pezizomycotina fungi, and R. oryzae is unique in the known fungi in possessing an hCyp33 orthologue and a TPR-containing FKBP. The repertoires of Cryptococcus neoformans, Aspergillus fumigatus, and Aspergillus nidulans were found to exhibit the highest orthology to the human repertoire, and Saccharomyces cerevisiae one of the lowest. CONCLUSION:Given this data, we would hypothesize that: (i) the evolution of the fungal PPIases is driven, at least in part, by the size of the proteome, (ii) evolutionary pressures differ both between the different PPIase families and the different fungi, and (iii) whilst the cyclophilins and parvulins have evolved to perform conserved functions, the FKBPs have evolved to perform more variable roles. Also, the repertoire of Cryptococcus neoformans may represent a better model fungal system within which to study the functions of the PPIases as its genome size and genetic tractability are equal to those of Saccharomyces cerevisiae, whilst its repertoires exhibits greater orthology to that of humans. However, further experimental investigations are required to confirm this.

Dataset Information

Peptidyl-prolyl cis-trans isomerase NIMA interacting 1 regulates skeletal muscle fusion through structural modification of Smad3 in the linker region.

Publications

Peptidyl-prolyl cis-trans isomerase NIMA interacting 1 regulates skeletal muscle fusion through structural modification of Smad3 in the linker region.

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