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Targeting of the same proteins to multiple subcellular destinations: mechanisms and physiological implications

2011; Wiley; Volume: 278; Issue: 22 Linguagem: Inglês

10.1111/j.1742-4658.2011.08355.x

1742-4658

Narayan G. Avadhani,

Endoplasmic Reticulum Stress and Disease

This minireview series summarizes mechanisms of bimodal targeting of different types of proteins and their pathophysiological consequences. Two reviews discuss mechanisms of targeting of drug inducible cytochrome P450s to endoplasmic reticulum and mitochondria. The third review discusses mechanisms of fumerase and other cystosolic soluble proteins to mitochondria and the cytosol and the fourth review discusses the mitochondrial localization of cytosolic glutathione S-transferases Protein targeting to different subcellular locations requires distinct signal sequences that are inbuilt in the protein, and also specific targeting machineries. The targeting signals for each subcellular compartment such as endoplasmic reticulum (ER), mitochondria, peroxisomes and nucleus are distinct and similarly the protein targeting machinery for each of these membrane compartments is different. However, it is becoming increasingly apparent that a large number of membrane associated and soluble proteins are targeted to multiple subcellular locations. Proteomic analyses reveal that yeast and mammalian mitochondria may contain 1000–1500 proteins, many of which lack canonical mitochondria targeting signals. Furthermore, a large fraction of yeast mitochondria associated proteins are also localized in other cellular compartments including the cytosol, nucleus, ER and peroxisomes. Proteins targeted to multiple cellular compartments include metabolic enzymes such as fumerase, aconitase, adenylate kinase, acetyl CoA desaturase, Mia4, catalase A, acyl CoA synthase, hydroxymethylglutaryl CoA lyase; regulatory protein kinases including protein kinase A, protein kinase C, GSK3, Akt, STAT3, AMPK; proteins involved in oncogenesis and apoptosis such as p53, BclXL, Bcl2; nuclear receptors such as estrogen receptor, GR, RXR; and pathogenic proteins such as prion protein and Alzheimer's amyloid precursor protein. The other proteins targeted to multiple subcellular compartments include proteins involved in anti-oxidant defense mechanism, glutathione S-transferase and glutathione peroxidase and cytochrome P450s (CYPs) that play a critical role in drug metabolism and chemical toxicity. In the case of prion protein and Alzheimer's amyloid precursor protein there is compelling evidence that their misplacement in the cytosol or mitochondria, respectively, plays critical roles in the pathogenesis of diseases. In the case of CYPs and fumerase, substantially altered catalytic properties are seen when these proteins are misplaced in the mitochondria and cytosol, respectively. Such proteins have been termed by other groups echoproteins or isoproteins. This series of four minireviews attempts to summarize mechanisms of bimodal targeting of different types of proteins and the pathophysiological consequences of bimodal targeting. The first review by Avadhani et al. summarizes mechanisms by which various xenobiotic inducible and constitutively expressed CYPs that are predominantly ER membrane associated are targeted to mitochondria by virtue of 'chimeric signals' they carry. The cryptic mitochondria targeting signals of these CYPs are activated either by endoprotease processing or by protein phosphorylation and the modified proteins are targeted preferentially to mitochondria. In the second review Yogev et al. discuss how the soluble 'echoprotein' (meaning same or iso proteins) forms of fumerase, aconitase and Nsf1 are localized in the yeast mitochondria and cytosol. They describe a process called reverse translocation wherein the proteins first enter mitochondria and then return to the cytosol. They also discuss the physiological significance of 'echoproteins' in the two cellular compartments. The third review by Raza describes how a family of cytosolic glutathione S-transferases is targeted to mitochondria in mammalian cells in response to various stress conditions. Mitochondrial translocation of these proteins is stimulated by protein kinase A or protein kinase C mediated phosphorylation which activates either the N-terminal or C-terminal cryptic targeting signals. The last review by Knockaert et al. describes the mechanism of mitochondria targeting of alcohol-inducible CYP2E1 and how the mitochondrial form may be playing roles in oxidative stress, alcohol toxicity and obesity.