细胞内所有的蛋白质和大多数的细胞外蛋白都在不断的进行更新, 即它们在不断地被降解, 并被新合成的蛋白质取代。细胞内蛋白的降解主要通过两个途径, 即自噬和泛素蛋白酶体系统。自噬是一种由溶酶体介导的细胞内过多或异常蛋白质的降解机制。在细胞内主要有3种类型的自噬, 即分子伴侣介导的自噬、微自噬和巨自噬。泛素蛋白酶体系统是由泛素介导的一种高度复杂的蛋白降解机制, 它参与降解细胞内许多蛋白质并且这个过程具有高度特异性。细胞内蛋白质的降解参与调节许多细胞过程, 包括细胞周期、DNA修复、细胞生长和分化、细胞质量的控制、病原生物的感染反应和细胞凋亡等。许多严重的人类疾病被认为是由于蛋白质降解系统的紊乱而引起的。文章综述了自噬和泛素化途径及其分子机制, 以及蛋白质降解系统紊乱的病理学意义。
All proteins in eukaryotic cells are continually being degraded and replaced. Autophagy and the ubiquitin-proteasome system are two mechanisms for intracellular protein degradation. Autophagy is mediated by lysosome, and is further divided into chaperone-mediated autophagy, microautophagy and macroautophagy. The ubiquitin-proteasome system is highly complex and mediated by ubiquitin, which participates in intracellular protein degradation in a specific manner. It is now known that degradation of intracellular proteins is involved in regulation of a series of cellular processes, including cell-cycle division, DNA repair, cell growth and differentiation, quality control, pathogen infection, and apoptosis. The aberrations in the protein degradation systems are involved in many serious human diseases. The present review sum-marizes the mechanisms of protein degradation and related human diseases.
[1] Lecker SH, Goldberg AL, Mitch WE. Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol, 2006, 17(7): 1807-1819.
[2] Luo H, Wong J, Wong B. Protein degradation systems in viral myocarditis leading to dilated cardiomyopathy. Cardiovasc Res, 2010, 85(2): 347-356.
[3] Wang CW, Klionsky DJ. The molecular mechanism of autophagy. Mol Med, 2003, 9(3-4): 65-76.
[4] Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N. The role of autophagy during the early neonatal starvation period. Nature, 2004, 432(7020): 1032-1036.
[5] Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell, 2004, 15(3): 1101-1111.
[6] Yorimitsu T, Klionsky DJ. Autophagy: molecular machinery for self-eating. Cell Death Differ, 2005, 12(Suppl. 2): 1542-1552.
[7] Kuma A, Mizushima N. Physiological role of autophagy as an intracellular recycling system: with an emphasis on nutrient metabolism. Semin Cell Dev Biol, 2010, 21(7): 683-690.
[8] Rabinowitz JD, White E. Autophagy and metabolism. Science, 2010, 330(6009): 1344-1348.
[9] Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol, 2007, 8(9): 741-752.
[10] Tanida I, Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol, 2004, 36(12): 2503-2518.
[11] Berry DL, Baehrecke EH. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell, 2007, 131(6): 1137-1148.
[12] Mathew R, Karp CM, Beaudoin B, Vuong N, Chen GH, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C, Dipaola RS, Karantza-Wadsworth V, White E. Autophagy suppresses tumorigenesis through elimination of p62. Cell, 2009, 137(6): 1062-1075.
[13] Okamoto K, Kondo-Okamoto N, Ohsumi Y. Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Dev Cell, 2009, 17(1): 87-97.
[14] Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol, 2010, 12(2): 119-131.
[15] Mizushima N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol, 2010, 22(2): 132-139.
[16] Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans, 2009, 37(Pt 1): 217-222.
[17] Arico S, Petiot A, Bauvy C, Dubbelhuis PF, Meijer AJ, Codogno P, Ogier-Denis E. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem, 2001, 276(38): 35243-35246.
[18] Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer, 2009, 9(8): 563-575.
[19] Liang JY, Shao SH, Xu ZX, Hennessy B, Ding ZY, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL, Slingerland JM, Mills GB. The energy sensing LKB1-AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol, 2007, 9(2): 218-224.
[20] Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol, 2011, 13(2): 132-141.
[21] Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science, 2011, 331(
