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OLA1 regulates protein synthesis and integrated stress response by inhibiting eIF2 ternary complex formation

Huarong Chen1, Renduo Song2, Guohui Wang2

  • 11] Department of Translational Imaging Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA [2] Cancer Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.

Scientific Reports
|August 19, 2015
PubMed

Insights

OLA1 is a novel GTPase that inhibits protein synthesis by blocking ternary complex formation. This discovery reveals a new mechanism for controlling the integrated stress response and impacts cancer cell survival and growth.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Translation is a critical cellular process, with its dysregulation linked to diseases like cancer.
  • The eukaryotic initiation factor 2 (eIF2) forms a ternary complex (TC) essential for translation initiation.
  • The integrated stress response (ISR) suppresses global translation and induces specific proteins, like ATF4, by limiting TC availability.

Purpose of the Study:

  • To identify novel regulators of translation initiation and the integrated stress response (ISR).
  • To elucidate the mechanism by which OLA1 influences eIF2 function and TC formation.
  • To investigate the role of OLA1 in cellular stress response and cancer progression.

Main Methods:

  • Biochemical assays to study OLA1's interaction with eIF2 and GTP hydrolysis.
  • Cellular experiments assessing ISR activation, protein synthesis, and cell survival under stress.
  • In vivo studies using cancer models to evaluate the impact of OLA1 depletion on tumor growth and metastasis.

Main Results:

  • OLA1 binds to eIF2, hydrolyzes GTP, and inhibits de novo ternary complex (TC) formation, representing a novel translational control mechanism.
  • Depletion of OLA1 resulted in a hypoactive ISR, increased cell survival under stress, and impaired cancer cell apoptosis.
  • In vivo, OLA1 knockdown promoted tumor growth and metastasis by reducing ISR and CHOP expression.

Conclusions:

  • OLA1 is a novel translational GTPase that negatively regulates protein synthesis and promotes the ISR.
  • OLA1 plays a critical role in controlling cell survival during stress and suppressing cancer progression.
  • Targeting OLA1 may offer a new therapeutic strategy for cancer treatment.

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