Global Proteome Remodeling during ER Stress Involves Hac1-Driven Expression of Long Undecoded Transcript Isoforms

Dev Cell. 2018 Jul 16;46(2):219-235.e8. doi: 10.1016/j.devcel.2018.06.016.


Cellular stress responses often require transcription-based activation of gene expression to promote cellular adaptation. Whether general mechanisms exist for stress-responsive gene downregulation is less clear. A recently defined mechanism enables both up- and downregulation of protein levels for distinct gene sets by the same transcription factor via coordinated induction of canonical mRNAs and long undecoded transcript isoforms (LUTIs). We analyzed parallel gene expression datasets to determine whether this mechanism contributes to the conserved Hac1-driven branch of the unfolded protein response (UPRER), indeed observing Hac1-dependent protein downregulation accompanying the upregulation of ER-related proteins that typifies UPRER activation. Proteins downregulated by Hac1-driven LUTIs include those with electron transport chain (ETC) function. Abrogated ETC function improves the fitness of UPRER-activated cells, suggesting functional importance to this regulation. We conclude that the UPRER drives large-scale proteome remodeling, including coordinated up- and downregulation of distinct protein classes, which is partly mediated by Hac1-induced LUTIs.

Keywords: ER stress; Hac1; LUTI; UPR; gene expression regulation; stress response; unfolded protein response.

Publication types

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

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Basic-Leucine Zipper Transcription Factors / physiology
  • Down-Regulation
  • Electron Transport Chain Complex Proteins / metabolism
  • Endoplasmic Reticulum / metabolism
  • Gene Expression Regulation, Fungal / genetics
  • Protein Folding
  • Protein Isoforms / metabolism
  • Proteome
  • RNA, Long Noncoding / metabolism*
  • RNA, Long Noncoding / physiology
  • RNA, Messenger / genetics
  • Repressor Proteins / metabolism*
  • Repressor Proteins / physiology
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Saccharomyces cerevisiae Proteins / physiology
  • Signal Transduction
  • Stress, Physiological / physiology
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Unfolded Protein Response / physiology*
  • Up-Regulation


  • Basic-Leucine Zipper Transcription Factors
  • Electron Transport Chain Complex Proteins
  • HAC1 protein, S cerevisiae
  • Protein Isoforms
  • Proteome
  • RNA, Long Noncoding
  • RNA, Messenger
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors