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Loss of Preproinsulin Interaction with Signal Recognition Particle Activates Protein Quality Control, Decreasing mRNA

Sarah C Miller1, Elena B Tikhonova1, Sarah M Hernandez1

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Journal of Molecular Biology
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Signal recognition particle (SRP) interacts with preproinsulin, impacting insulin production. This study reveals SRP

Keywords:
protein secretionprotein transportsecretory proteinssignal peptidesignal recognition particle (SRP)

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Area of Science:

  • Molecular Biology
  • Genetics
  • Endocrinology

Background:

  • Monogenic diabetes results from insulin gene variants, but mechanisms are often unclear.
  • Preproinsulin synthesis involves a signal peptide (SP) recognized by signal recognition particle (SRP) or alternative pathways.
  • The precise role of SRP in preproinsulin biogenesis remains debated.

Purpose of the Study:

  • To investigate the interaction between SRP and preproinsulin signal peptide.
  • To elucidate the role of SRP and RAPP in insulin biogenesis and disease pathogenesis.
  • To analyze the impact of disease-causing mutations in the preproinsulin SP.

Main Methods:

  • Site-specific photocrosslinking to detect SRP-preproinsulin SP interaction.
  • SRP54 depletion to assess effects on insulin mRNA and protein levels.
  • Analysis of five disease-causing preproinsulin SP mutations.

Main Results:

  • SRP subunit SRP54 directly interacts with the preproinsulin SP.
  • SRP54 depletion reduces insulin mRNA and protein expression, implicating RAPP in quality control.
  • Mutation effects correlate with SP position and severity, suggesting diverse pathogenic mechanisms.
  • The RAPP pathway is implicated in neonatal diabetes caused by the Leu13Arg mutation.

Conclusions:

  • SRP is involved in preproinsulin biogenesis via SRP54 interaction with the SP.
  • RAPP protein quality control pathway plays a role in insulin biogenesis.
  • Disease-causing mutations in the preproinsulin SP exhibit varied molecular mechanisms.