論文

国際誌
2020年7月29日

The Tudor-domain protein TDRD7, mutated in congenital cataract, controls the heat shock protein HSPB1 (HSP27) and lens fiber cell morphology.

Human molecular genetics
  • Carrie E Barnum
  • ,
  • Salma Al Saai
  • ,
  • Shaili D Patel
  • ,
  • Catherine Cheng
  • ,
  • Deepti Anand
  • ,
  • Xiaolu Xu
  • ,
  • Soma Dash
  • ,
  • Archana D Siddam
  • ,
  • Lisa Glazewski
  • ,
  • Emily Paglione
  • ,
  • Shawn W Polson
  • ,
  • Shinichiro Chuma
  • ,
  • Robert W Mason
  • ,
  • Shuo Wei
  • ,
  • Mona Batish
  • ,
  • Velia M Fowler
  • ,
  • Salil A Lachke

29
12
開始ページ
2076
終了ページ
2097
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1093/hmg/ddaa096

Mutations of the RNA granule component TDRD7 (OMIM: 611258) cause pediatric cataract. We applied an integrated approach to uncover the molecular pathology of cataract in Tdrd7-/- mice. Early postnatal Tdrd7-/- animals precipitously develop cataract suggesting a global-level breakdown/misregulation of key cellular processes. High-throughput RNA sequencing integrated with iSyTE-bioinformatics analysis identified the molecular chaperone and cytoskeletal modulator, HSPB1, among high-priority downregulated candidates in Tdrd7-/- lens. A protein fluorescence two-dimensional difference in-gel electrophoresis (2D-DIGE)-coupled mass spectrometry screen also identified HSPB1 downregulation, offering independent support for its importance to Tdrd7-/- cataractogenesis. Lens fiber cells normally undergo nuclear degradation for transparency, posing a challenge: how is their cell morphology, also critical for transparency, controlled post-nuclear degradation? HSPB1 functions in cytoskeletal maintenance, and its reduction in Tdrd7-/- lens precedes cataract, suggesting cytoskeletal defects may contribute to Tdrd7-/- cataract. In agreement, scanning electron microscopy (SEM) revealed abnormal fiber cell morphology in Tdrd7-/- lenses. Further, abnormal phalloidin and wheat germ agglutinin (WGA) staining of Tdrd7-/- fiber cells, particularly those exhibiting nuclear degradation, reveals distinct regulatory mechanisms control F-actin cytoskeletal and/or membrane maintenance in post-organelle degradation maturation stage fiber cells. Indeed, RNA immunoprecipitation identified Hspb1 mRNA in wild-type lens lysate TDRD7-pulldowns, and single-molecule RNA imaging showed co-localization of TDRD7 protein with cytoplasmic Hspb1 mRNA in differentiating fiber cells, suggesting that TDRD7-ribonucleoprotein complexes may be involved in optimal buildup of key factors. Finally, Hspb1 knockdown in Xenopus causes eye/lens defects. Together, these data uncover TDRD7's novel upstream role in elevation of stress-responsive chaperones for cytoskeletal maintenance in post-nuclear degradation lens fiber cells, perturbation of which causes early-onset cataracts.

リンク情報
DOI
https://doi.org/10.1093/hmg/ddaa096
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32420594
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390939

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