Heat shock protein 60 couples an oxidative stress-responsive p38/MK2 signaling and NF-κB survival machinery in cancer cells

Seongchun Min, Ji Yeon Kim, Hyo Min Cho, Sujin Park, Ji Min Hwang, Hyejin You, Young Chan Chae, Won Jae Lee, Woong Sun, Dongmin Kang, Sanghyuk Lee, Sang Won Kang

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondria communicate with other cellular compartments via the secretion of protein factors. Here, we report an unexpected messenger role for heat shock protein 60 (HSP60) as a mitochondrial-releasing protein factor that couples stress-sensing signaling and cell survival machineries. We show that mild oxidative stress predominantly activates the p38/MK2 complex, which phosphorylates mitochondrial fission factor 1 (MFF1) at the S155 site. Such phosphorylated MFF1 leads to the oligomerization of voltage anion-selective channel 1, thereby triggering the formation of a mitochondrial membrane pore through which the matrix protein HSP60 passes. The liberated HSP60 associates with and activates the IκB kinase (IKK) complex in the cytosol, which consequently induces the NF-κB-dependent expression of survival genes in nucleus. Indeed, inhibition of the HSP60 release or HSP60-IKK interaction sensitizes the cancer cells to mild oxidative stress and regresses the tumorigenic growth of cancer cells in the mouse xenograft model. Thus, this study reveals a novel mitonuclear survival axis responding to oxidative stress.

Original languageEnglish
Article number102293
JournalRedox Biology
Volume51
DOIs
Publication statusPublished - 2022 May

Keywords

  • HSP60
  • Mitochondria
  • NF-κB
  • Oxidative stress
  • p38 MAPK

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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