NEDD4-mediated HSF1 degradation underlies α-synucleinopathy.
Cellular protein homeostasis is achieved by a delicate network of molecular chaperones and various proteolytic processes such as ubiquitin-proteasome system (UPS) to avoid a build-up of misfolded protein aggregates. The latter is a common denominator of neurodegeneration. Neurons are found to be particularly vulnerable to toxic stress from aggregation-prone proteins such as α-synuclein. Induction of heat-shock proteins (HSPs), such as through activated heat shock transcription factor 1 (HSF1) via Hsp90 inhibition, is being investigated as a therapeutic option for proteinopathic diseases. HSF1 is a master stress-protective transcription factor which activates genes encoding protein chaperones (e.g. iHsp70) and anti-apoptotic proteins. However, whether and how HSF1 is dysregulated during neurodegeneration has not been studied. Here, we discover aberrant HSF1 degradation by aggregated α-synuclein (or α-synuclein-induced proteotoxic stress) in transfected neuroblastoma cells. HSF1 dysregulation via α-synuclein was confirmed by in vivo assessment of mouse and in situ studies of human specimens with α-synucleinopathy. We demonstrate that elevated NEDD4 is implicated as the responsible ubiquitin E3 ligase for HSF1 degradation through UPS. Furthermore, pharmacologically induced SIRT1-mediated deacetylation can attenuate aberrant NEDD4-mediated HSF1 degradation. Indeed, we define the acetylation status of the Lys 80 residue located in the DNA-binding domain of HSF1 as a critical factor in modulating HSF1 protein stability in addition to its previously identified role in the transcriptional activity. Together with the finding that preserving HSF1 can alleviate α-synuclein toxicity, this study strongly suggests that aberrant HSF1 degradation is a key neurodegenerative mechanism underlying α-synucleinopathy.
Department of Pharmacology and Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN 38163, USA.
Eunhee
E
Kim
Department of Pharmacology and Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN 38163, USA.
Bin
B
Wang
Transgenics Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Namratha
N
Sastry
Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA.
Eliezer
E
Masliah
Department of Neurology, Sanders-Brown Center on Aging, 800 South Limestone Street, Lexington, KY 40536, USA and.
Peter T
PT
Nelson
Transgenics Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Huaibin
H
Cai
Department of Pharmacology and Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, 874 Union Avenue/Crowe 401, Memphis, TN 38163, USA, fliao@uthsc.edu.
Francesca-Fang
FF
Liao
D000107:Acetylation; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D000076249:Heat Shock Transcription Factors; D006801:Humans; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D046988:Proteasome Endopeptidase Complex; D059748:Proteolysis; D057165:Proteostasis Deficiencies / Q000378:metabolism* / Q000473:pathology; D056564:Sirtuin 1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D051844:alpha-Synuclein
D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors; D051844:alpha-Synuclein; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D056564:Sirtuin 1