Nature：自噬作用与泛素—蛋白酶体系统之间的关系
生物谷报道：对于一个细胞来说，要除去随着时间推移所积累的不合适的蛋白主要有两个通道：泛素—蛋白酶体系统和自噬作用，后者指的是通过一个细胞自身的溶酶体细胞器来使该细胞自己的组成部分自我破坏。用泛素—蛋白酶体系统已被瓦解了的一种神经退化疾病的果蝇模型所作的研究表明，自噬作用可以补偿这种损失。两个蛋白破坏通道在体内是联系在一起的，与微管相关的组蛋白去乙酰化酶HDAC6充当二者之间的联系。HDAC6的表达足以诱发自噬作用，使果蝇的神经退化得以挽救。这些发现反映了自噬作用与泛素—蛋白酶体系统之间的关系，并且对于了解与蛋白有关的神经退化疾病的发病机理及可能的治疗方法也有参考意义。（引自 Nature asia）
原始出处:
Nature 447, 860-864 (14 June 2007) | doi:10.1038/nature05853; Received 19 December 2006; Accepted 16 April 2007
HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS
Udai Bhan Pandey1, Zhiping Nie1, Yakup Batlevi2, Brett A. McCray1, Gillian P. Ritson1, Natalia B. Nedelsky1, Stephanie L. Schwartz1, Nicholas A. DiProspero3, Melanie A. Knight3, Oren Schuldiner4, Ranjani Padmanabhan5, Marc Hild5, Deborah L. Berry2, Dan Garza5, Charlotte C. Hubbert6, Tso-Pang Yao6, Eric H. Baehrecke2 & J. Paul Taylor1
- Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
- Center for Biosystems Research, University of Maryland Biotechnology Institute, College Park, Maryland 20742, USA
- Neurogenetics Branch, NINDS, NIH, Bethesda, Maryland 20817, USA
- Department of Biological Sciences, Stanford University, Stanford, California 94305, USA
- Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA
Correspondence to: J. Paul Taylor1 Correspondence and requests for materials should be addressed to J.P.T. (Email: jpt@mail.med.upenn.edu).
A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons1. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration2. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway3. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection4, 5. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology6, 7, 8, 9. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins10, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.
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