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GET3 regulates apoptosis via tail-anchoring of MCL1

Chun Yin Yu1, Mingxuan Du1, Tsz Kwan Yeung1

  • 1Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.

Cell Death and Differentiation
|May 7, 2026
PubMed

Insights

The GET pathway regulates apoptosis by controlling MCL1, a key protein. GET3 depletion impacts cell cycle and survival, highlighting MCL1

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The BCL2-like protein MCL1 is crucial for apoptosis and other cellular functions.
  • Many BCL2 family proteins are tail-anchored (TA) proteins, but MCL1's membrane targeting mechanism is unclear.
  • The Guided Entry (GET) pathway is a primary route for TA protein membrane insertion.

Purpose of the Study:

  • To investigate the role of the GET pathway, specifically GET3 (ASNA1/TRC40), in regulating MCL1 and apoptosis.
  • To determine if MCL1 is a tail-anchored cargo of the GET pathway.
  • To elucidate the functional consequences of GET3 deficiency on cell cycle, apoptosis, and survival.

Main Methods:

  • Utilized degron-mediated depletion of GET3 in human cell lines (HeLa and RPE1).
  • Assessed cell cycle progression, apoptosis markers, and clonogenic survival.
  • Performed co-immunoprecipitation to detect interactions between GET3 and MCL1.
  • Investigated MCL1 expression levels under GET3 depletion and overexpression conditions.

Main Results:

  • GET3 depletion caused cell cycle arrest in HeLa and RPE1 cells.
  • GET3 deficiency led to increased apoptosis and reduced survival, particularly in HeLa cells.
  • MCL1 expression decreased with GET3 depletion and increased with GET3 overexpression, indicating MCL1 is a GET3 cargo.
  • Direct interaction between GET3 and MCL1's C-terminal tail was confirmed.
  • GET3 depletion exacerbated apoptosis induced by MCL1 inhibitors and prolonged mitotic arrest.

Conclusions:

  • The GET pathway, via GET3, plays a significant role in regulating apoptosis.
  • MCL1 is a tail-anchored protein targeted by the GET pathway.
  • GET3 deficiency sensitizes cells to apoptosis, especially under stress conditions involving MCL1 inhibition or mitotic arrest.

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