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<p>The BCL2-like protein MCL1 plays pivotal roles in apoptosis and non-apoptotic functions. While many BCL2 family members are predicted to be tail-anchored (TA) proteins, direct evidence for MCL1’s membrane targeting via the GET pathway, a major pathway for membrane insertion of TA proteins, has been lacking. Using degron-mediated depletion of GET3 (ASNA1/TRC40) in human cell lines, we uncovered a role of GET3 in regulating apoptosis. Depleting GET3 induced a slowdown of the cell cycle in HeLa and non-cancerous RPE1 cells. However, GET3 deficiency induced a more pronounced toxicity in HeLa cells, marked by enhanced apoptosis and reduced clonogenic survival. Notably, MCL1 expression diminished upon GET3 depletion and increased with GET3 overexpression, suggesting that MCL1 may be a TA-containing cargo of GET3. Moreover, we observed a direct interaction between GET3 and MCL1 via the C-terminal hydrophobic tail. Functionally, GET3 depletion enhanced apoptosis triggered by pharmaceutical inhibition of MCL1. Furthermore, GET3 deficiency promoted MCL1 downregulation and accelerated apoptosis during prolonged mitotic arrest. These findings underscore the importance of the GET pathway in regulating apoptosis and MCL1’s tail-anchoring.</p>

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GET3 regulates apoptosis via tail-anchoring of MCL1

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月7日

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  • Chun Yin Yu,
  • Mingxuan Du,
  • Tsz Kwan Yeung,
  • Randy Yat Choi Poon

摘要

The BCL2-like protein MCL1 plays pivotal roles in apoptosis and non-apoptotic functions. While many BCL2 family members are predicted to be tail-anchored (TA) proteins, direct evidence for MCL1’s membrane targeting via the GET pathway, a major pathway for membrane insertion of TA proteins, has been lacking. Using degron-mediated depletion of GET3 (ASNA1/TRC40) in human cell lines, we uncovered a role of GET3 in regulating apoptosis. Depleting GET3 induced a slowdown of the cell cycle in HeLa and non-cancerous RPE1 cells. However, GET3 deficiency induced a more pronounced toxicity in HeLa cells, marked by enhanced apoptosis and reduced clonogenic survival. Notably, MCL1 expression diminished upon GET3 depletion and increased with GET3 overexpression, suggesting that MCL1 may be a TA-containing cargo of GET3. Moreover, we observed a direct interaction between GET3 and MCL1 via the C-terminal hydrophobic tail. Functionally, GET3 depletion enhanced apoptosis triggered by pharmaceutical inhibition of MCL1. Furthermore, GET3 deficiency promoted MCL1 downregulation and accelerated apoptosis during prolonged mitotic arrest. These findings underscore the importance of the GET pathway in regulating apoptosis and MCL1’s tail-anchoring.