Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome.
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.
Ding
Wen-Xing
WX
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15231, USA.
Yin
Xiao-Ming
XM
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D017510:Protein Folding; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D021381:Protein Transport; D011506:Proteins / Q000145:classification / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D054875:Ubiquitination / Q000502:physiology
D011506:Proteins; D046988:Proteasome Endopeptidase Complex