2. Academic Validation
  3. TOR signaling regulates liquid phase separation of the SMN complex governing snRNP biogenesis

TOR signaling regulates liquid phase separation of the SMN complex governing snRNP biogenesis

  • Cell Rep. 2021 Jun 22;35(12):109277. doi: 10.1016/j.celrep.2021.109277.
Maximilian Schilling 1,  Archana B Prusty 2,  Björn Boysen 3,  Felix S Oppermann 4,  Yannick L Riedel 1,  Alma Husedzinovic 3,  Homa Rasouli 4,  Angelika König 1,  Pradhipa Ramanathan 2,  Jürgen Reymann 5,  Holger Erfle 5,  Henrik Daub 4,  Utz Fischer 2,  Oliver J Gruss 6
Affiliations

Affiliations

  • 1 Institut für Genetik, Rheinische Friedrich-Wilhelms Universität Bonn, 53115 Bonn, Germany.
  • 2 Theodor Boveri Institute, Biocenter of the University of Würzburg, 97074 Würzburg, Germany.
  • 3 Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
  • 4 Evotec SE, Am Klopferspitz 19a, 82152 Martinsried, Germany.
  • 5 Advanced Biological Screening Facility, BioQuant Centre, Universität Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
  • 6 Institut für Genetik, Rheinische Friedrich-Wilhelms Universität Bonn, 53115 Bonn, Germany; Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany. Electronic address: [email protected].
PMID: 34161763 DOI: 10.1016/j.celrep.2021.109277
Abstract

The activity of the SMN complex in promoting the assembly of pre-mRNA processing UsnRNPs correlates with condensation of the complex in nuclear Cajal bodies. While mechanistic details of its activity have been elucidated, the molecular basis for condensation remains unclear. High SMN complex phosphorylation suggests extensive regulation. Here, we report on systematic siRNA-based screening for modulators of the capacity of SMN to condense in Cajal bodies and identify mTOR and ribosomal protein S6 kinase β-1 as key regulators. Proteomic analysis reveals TOR-dependent phosphorylations in SMN complex subunits. Using stably expressed or optogenetically controlled phospho mutants, we demonstrate that serine 49 and 63 phosphorylation of human SMN controls the capacity of the complex to condense in Cajal bodies via liquid-liquid phase separation. Our findings link SMN complex condensation and UsnRNP biogenesis to cellular energy levels and suggest modulation of TOR signaling as a rational concept for therapy of the SMN-linked neuromuscular disorder spinal muscular atrophy.

Keywords

Cajal body; LLPS; SMA; SMN; assembly of ribonucleoprotein complexes; mTOR; optogenetics; phase separation; ribosomal protein S6-kinase β-1 (RPS6KB1); snRNP.

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