A unique mode of keratinocyte death requires intracellular acidification

Takeshi Matsui, Nanako Kadono-Maekubo, Yoshiro Suzuki, Yuki Furuichi, Keiichiro Shiraga, Hiroyuki Sasaki, Azusa Ishida, Sonoko Takahashi, Takaharu Okada, Kiminori Toyooka, Jafar Sharif, Takaya Abe, Hiroshi Kiyonari, Makoto Tominaga, Atsushi Miyawaki, Masayuki Amagai

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)


The stratum corneum (SC), the outermost epidermal layer, consists of nonviable anuclear keratinocytes, called corneocytes, which function as a protective barrier. The exact modes of cell death executed by keratinocytes of the upper stratum granulosum (SG1 cells) remain largely unknown. Here, using intravital imaging combined with intracellular Ca2+- and pH-responsive fluorescent probes, we aimed to dissect the SG1 death process in vivo. We found that SG1 cell death was preceded by prolonged (∼60 min) Ca2+ elevation and rapid induction of intracellular acidification. Once such intracellular ionic changes were initiated, they became sustained, irreversibly committing the SG1 cells to corneocyte conversion. Time-lapse imaging of isolated murine SG1 cells revealed that intracellular acidification was essential for the degradation of keratohyalin granules and nuclear DNA, phenomena specific to SC corneocyte formation. Furthermore, intravital imaging showed that the number of SG1 cells exhibiting Ca2+ elevation and the timing of intracellular acidification were both tightly regulated by the transient receptor potential cation channel V3. The functional activity of this protein was confirmed in isolated SG1 cells using whole-cell patch-clamp analysis. These findings provide a theoretical framework for improved understanding of the unique molecular mechanisms underlying keratinocyte-specific death mode, namely corneoptosis.

Original languageEnglish
Article numbere2020722118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
Publication statusPublished - 2021 Apr 27


  • Acidification
  • Cell death
  • Corneoptosis
  • Cornification
  • Keratinocytes

ASJC Scopus subject areas

  • General


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