The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1

Nat Cell Biol. 2022 Jan;24(1):74-87. doi: 10.1038/s41556-021-00813-8. Epub 2022 Jan 13.

Abstract

Heavy metals are both integral parts of cells and environmental toxicants, and their deregulation is associated with severe cellular dysfunction and various diseases. Here we show that the Hippo pathway plays a critical role in regulating heavy metal homeostasis. Hippo signalling deficiency promotes the transcription of heavy metal response genes and protects cells from heavy metal-induced toxicity, a process independent of its classic downstream effectors YAP and TAZ. Mechanistically, the Hippo pathway kinase LATS phosphorylates and inhibits MTF1, an essential transcription factor in the heavy metal response, resulting in the loss of heavy metal response gene transcription and cellular protection. Moreover, LATS activity is inhibited following heavy metal treatment, where accumulated zinc directly binds and inhibits LATS. Together, our study reveals an interplay between the Hippo pathway and heavy metals, providing insights into this growth-related pathway in tissue homeostasis and stress response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadmium / metabolism*
  • Cadmium / toxicity
  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation / genetics
  • HEK293 Cells
  • HeLa Cells
  • Hippo Signaling Pathway / physiology*
  • Homeostasis / genetics
  • Humans
  • Inactivation, Metabolic / physiology
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Stress, Physiological / physiology
  • Transcription Factors / metabolism*
  • Transcription, Genetic / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Zinc / metabolism*
  • Zinc / toxicity

Substances

  • DNA-Binding Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • transcription factor MTF-1
  • Cadmium
  • LATS1 protein, human
  • LATS2 protein, human
  • Protein Serine-Threonine Kinases
  • Zinc