Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome

Wen Xing Ding, Xiao Ming Yin

Research output: Contribution to journalReview article

251 Scopus citations


Based on a functional categorization, proteins may be grouped into three types and sorted to either the proteasome or the macroautophagy pathway for degradation. The two pathways are mechanistically connected but their capacity seems different. Macroautophagy can degrade all forms of misfolded proteins whereas proteasomal degradation is likely limited to soluble ones. Unlike the bulk protein degradation that occurs during starvation, autophagic degradation of misfolded proteins can have a degree of specificity, determined by ubiquitin modification and the interactions of p62/SQSTM1 and HDAC6. Macroautophagy is initiated in response to endoplasmic reticulum (ER) stress caused by misfolded proteins, via the ER-activated autophagy (ERAA) pathway, which activates a partial unfolded protein response involving PERK and/or IRE1, and a calcium-mediated signaling cascade. ERAA serves the function of mitigating ER stress and suppressing cell death, which may be explored for controlling protein conformational diseases. Conversely, inhibition of ERAA may be explored for sensitizing resistant tumor cells to cytotoxic agents.

Original languageEnglish (US)
Pages (from-to)141-150
Number of pages10
Issue number2
StatePublished - Feb 16 2008



  • Apoptosis
  • Cancer
  • Conformational disease
  • ER-associated degradation
  • Endoplasmic reticulum stress
  • Macroautophagy
  • Misfolded proteins
  • Neurodegenerative disease
  • Proteasome
  • Unfolded protein response

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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