Miz1 is required to maintain autophagic flux

Nat Commun. 2013:4:2535. doi: 10.1038/ncomms3535.

Abstract

Miz1 is a zinc finger protein that regulates the expression of cell cycle inhibitors as part of a complex with Myc. Cell cycle-independent functions of Miz1 are poorly understood. Here we use a Nestin-Cre transgene to delete an essential domain of Miz1 in the central nervous system (Miz1(ΔPOZNes)). Miz1(ΔPOZNes) mice display cerebellar neurodegeneration characterized by the progressive loss of Purkinje cells. Chromatin immunoprecipitation sequencing and biochemical analyses show that Miz1 activates transcription upon binding to a non-palindromic sequence present in core promoters. Target genes of Miz1 encode regulators of autophagy and proteins involved in vesicular transport that are required for autophagy. Miz1(ΔPOZ) neuronal progenitors and fibroblasts show reduced autophagic flux. Consistently, polyubiquitinated proteins and p62/Sqtm1 accumulate in the cerebella of Miz1(ΔPOZNes) mice, characteristic features of defective autophagy. Our data suggest that Miz1 may link cell growth and ribosome biogenesis to the transcriptional regulation of vesicular transport and autophagy.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Autophagy / genetics*
  • Binding Sites
  • Cerebellum / metabolism*
  • Cerebellum / pathology
  • Female
  • Gene Expression Regulation
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Integrases / genetics
  • Integrases / metabolism
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Inhibitors of Activated STAT / genetics*
  • Protein Inhibitors of Activated STAT / metabolism
  • Protein Structure, Tertiary
  • Purkinje Cells / metabolism*
  • Purkinje Cells / pathology
  • Ribosomes / metabolism
  • Sequence Analysis, DNA
  • Sequestosome-1 Protein
  • Signal Transduction
  • Transcription Factor TFIIH
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transport Vesicles / metabolism*
  • Ubiquitin-Protein Ligases
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Gtf2h1 protein, mouse
  • Heat-Shock Proteins
  • Nuclear Proteins
  • Protein Inhibitors of Activated STAT
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Transcription Factors
  • Transcription Factor TFIIH
  • Miz1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Cre recombinase
  • Integrases