p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

Pellegrini, Michela; Finetti, Francesca; Petronilli, Valeria; Ulivieri, Cristina; Giusti, F; Lupetti, Pietro; Giorgio, Marco; Pelicci, PierGiuseppe; Bernardi, Paolo; Baldari, Cosima T.

doi:10.1038/sj.cdd.4401997

Cited by 48 publications

(47 citation statements)

References 38 publications

(61 reference statements)

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“…In the intermembrane space, electron transfer between cytochrome c and activated p66Shc results in ROS generation that can initiate mitochondrial-induced apoptosis [35] (Figure 2). Although p66Shc-triggered ROS production is initiated by Ca 2+ and accompanied by alterations in mitochondrial Ca 2+ homeostasis [36], its effect on mitochondria does not necessarily depend on cytosolic Ca 2+ elevation [37]. In fact, deletion of the p66Shc longevity gene has been associated with reduced systemic and organ oxidative stress and a delay in the development of atherosclerosis in high-fat-fed mice [38], indicating the potential involvement of p66Shc in lipid-associated vascular disease and lipotoxicity.…”

Section: P66shc As a Link Between Cytosolic Protein Phosphorylation Amentioning

confidence: 99%

Mitochondrial protein phosphorylation: instigator or target of lipotoxicity?

Graier

Malli

Kostner

2009

Trends in Endocrinology & Metabolism

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Lipotoxicity occurs as a consequence of chronic exposure of non-adipose tissue and cells to elevated concentrations of fatty acids, triglycerides and/or cholesterol. The contribution of mitochondria to lipotoxic cell dysfunction, damage and death is associated with elevated production of reactive oxygen species and initiation of apoptosis. Although there is a broad consensus on the involvement of these phenomena with lipotoxicity, the molecular mechanisms that initiate, mediate and trigger mitochondrial dysfunction in response to substrate overload remain unclear. Here, we focus on protein phosphorylation as an important phenomenon in lipotoxicity that harms mitochondria-related signal transduction and integration in cellular metabolism. Moreover, the degradation of mitochondria by mitophagy is discussed as an important landmark that leads to cellular apoptosis in lipotoxicity. Mitochondrial relay functionThe term 'lipotoxicity' describes the dysfunction of non-adipose tissue and cells that face chronic exposure to elevated fatty acids, triglycerides and/or cholesterol [1][2][3]. When plasma levels of prandial and postprandial fatty acids, triglycerides or cholesterol exceed the uptake capacity of adipose tissue, non-adipose tissue becomes overloaded with lipids, resulting in several metabolic imbalances and/or diseases. Once the oxidative capacity of these cells is exhausted, lipotoxic pathways are initiated that yield cellular dysfunction and, at worst, result in cell death. Although multiple lipotoxic events have been described [1][2][3] (e.g. induction of endoplasmic reticulum stress [4,5] by disruption of its structural integrity [6]) recent findings point to mitochondrial dysfunction as a key phenomenon in lipotoxicity leading to ominous signals [7][8][9][10][11].The mitochondria not only serve as the power plant of the cell but also act as a cellular relay, sensing multiple cellular and environmental parameters, including energy status, oxygen availability and activation patterns of cellular signal-transduction pathways. Mitochondria then integrate these inputs, adapting their activity and functions to, ultimately, tune cellular responsiveness with respect to the current demand of the cell [12] (Figure 1). In spite of the important tasks of the mitochondrion and in contrast to its functions in energy metabolism, its contribution to signal transduction has not been thoroughly investigated, and the [24,25]. Because similar pathways were also described as leading to cellular differentiation [17], the actual physiological outcome might depend on the pattern of activated pathways rather than on a single phenomenon. Thus, it is feasible that changes in the mitochondrial phosphoproteome caused by alterations in kinase activities are fundamental for the decisive setting of signaling patterns for cell survival or the initiation of cellular dysfunction in lipotoxicity leading to cell death. Three different scenarios affecting mitochondrial protein phosphorylation can be postulated in lipotoxicity ( Figure ...

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Section: P66shc As a Link Between Cytosolic Protein Phosphorylation Amentioning

confidence: 99%

Mitochondrial protein phosphorylation: instigator or target of lipotoxicity?

Graier

Malli

Kostner

2009

Trends in Endocrinology & Metabolism

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“…19 Of these, the first involves dissipation of mitochondrial transmembrane potential and cytochrome c release due to an imbalance in the expression levels of proapoptotic/antiapoptotic Bcl-2 family members, 19 while the second involves Ca 2ϩ deregulation due to decreased expression and activity of plasma membrane Ca 2ϩ ATPases through the ROSelevating activity of p66Shc. 20 Submitted December 22, 2007; accepted March 7, 2008. Prepublished online as Blood First Edition paper, March 11, 2008; DOI 10.1182 DOI 10.…”

Section: Introductionmentioning

confidence: 99%

“…19 Of these, the first involves dissipation of mitochondrial transmembrane potential and cytochrome c release due to an imbalance in the expression levels of proapoptotic/antiapoptotic Bcl-2 family members, 19 while the second involves Ca 2ϩ deregulation due to decreased expression and activity of plasma membrane Ca 2ϩ ATPases through the ROSelevating activity of p66Shc. 20 The defects found in p66Shc Ϫ/Ϫ T cells, as well as their enhanced proliferative responses to TCR agonists, suggest a potential impact of p66Shc deficiency in immune repertoire selection and lymphocyte homeostasis. Here we show that p66Shc Ϫ/Ϫ mice harbor spontaneous lymphocyte activation and develop a lupus-like autoimmune disease.…”

Section: Introductionmentioning

confidence: 99%

The proapoptotic and antimitogenic protein p66SHC acts as a negative regulator of lymphocyte activation and autoimmunity

Finetti

Pellegrini

Ulivieri

et al. 2008

Blood

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The ShcA locus encodes 3 protein isoforms that differ in tissue specificity, subcellular localization, and function. Among these, p66Shc inhibits TCR coupling to the Ras/MAPK pathway and primes T cells to undergo apoptotic death. We have investigated the outcome of p66Shc deficiency on lymphocyte development and homeostasis. We show that p66Shc ؊/؊ mice develop an age-related lupus-like autoimmune disease characterized by spontaneous peripheral T-and B-cell activation and proliferation, autoantibody production, and immune complex deposition in kidney and skin, resulting in autoimmune glomerulonephritis and alopecia. IntroductionThe Shc protein family includes 4 members, ShcA, ShcB, ShcC, and RaLP. 1,2 ShcA is expressed as 3 isoforms of 52, 46, and 66 kDa, which display the PTB-CH1-SH2 Shc family signature, preceded in p66Shc by a CH2 domain containing a phosphorylatable serine (Ser36) 3 and a cytochrome c-binding region within the CH2-PTB domains. 4 In addition to structural differences, p52Shc/p46Shc differ from p66Shc in expression and function. The shorter isoforms are constitutively and ubiquitously expressed, whereas p66Shc expression is regulated by an alternative promoter 5 and is tissue restricted. 6 ShcA isoforms differ also in their subcellular localization and function. p52Shc is a cytosolic protein acting as adaptor in pathways triggered by surface receptors controlling proliferation, chemotaxis, and survival. 7,8 p46Shc localizes to mitochondria, where it subserves an unknown function. 9 On the other hand, p66Shc is expressed as 2 pools, one cytosolic and the other mitochondrial, and is endowed with antimitogenic and proapoptotic activities. Indeed, p66Shc inhibits activation of the Ras/MAPK pathway by tyrosine kinase receptors and the T-cell antigen receptor (TCR) by competing with p52Shc. Furthermore, in fibroblasts, p66Shc participates in oxidative stress-induced apoptosis by triggering the mitochondrial pathway as a p53 target. 10 p66Shc-mediated apoptosis is dependent on Ser36 phosphorylation, which is mediated by PKC␤ and required for p66Shc translocation from the cytosol to mitochondria by the prolylisomerase Pin1. 11 In mitochondria, p66Shc is maintained in an inactive state within a high-molecular-mass complex, which includes the TIM-TOM import complex and Hsp70. Following proapoptotic stimulation, p66Shc is released and acquires the capacity to oxidize cytochrome c and catalyze H 2 O 2 production, leading to mitochondrial dysfunction, opening of the permeability transition pore (PTP), and apoptosis. 4,12 Moreover, p66Shc modulates the levels of reactive oxygen species (ROSs) by suppressing activation of FKHRL1, a forkhead transcription factor that controls catalase expression and is implicated as such in H 2 O 2 scavenging. 13 Alterations in oxidative metabolism in p66Shc Ϫ/Ϫ fibroblasts, characterized by decreased mitochondriadependent energy generation and increased aerobic glycolysis, 14 also contribute to the reduction in ROS levels observed in these cells. In agreement with the capac...

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“…Opposite to the positive role exerted by p52Shc in Ag-receptor signaling, we recently showed that the 66-kDa isoform, which is expressed in lymphocytes and monocytes, albeit at lower levels compared with p52/p46Shc, inhibits TCR/BCR-dependent activation of the Ras-MAPK pathway and promotes T and B cell apoptosis (17,18). Furthermore, we demonstrated that ablation of the p66shc gene in mice leads to spontaneous lymphocyte activation and development of a lupus-like autoimmune disease, indicating a key role for p66Shc in controlling lymphocyte homeostasis (19).…”

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confidence: 99%

p66Shc Is a Negative Regulator of FcεRI-Dependent Signaling in Mast Cells

Ulivieri

Fanigliulo

Masi

et al. 2011

The Journal of Immunology

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Aggregation of FcεRI on mast cells activates signaling pathways, resulting in degranulation and cytokine release. Release of mast cell-derived inflammatory mediators is tightly regulated by the interplay of positive and negative signals largely orchestrated by adapter proteins. Among these, the Shc family adapter p52Shc, which couples immunoreceptors to Ras activation, positively regulates FcεRI-dependent signaling. Conversely, p66Shc was shown to uncouple the TCR for the Ras–MAPK pathway and prime T cells to undergo apoptotic death. Loss of p66Shc in mice results in breaking of immunologic tolerance and development of lupus-like autoimmune disease, which includes alopecia among its pathological manifestations. The presence of numerous activated mast cells in alopecic skin areas suggests a role for this adapter in mast cells. In this study, we addressed the involvement of p66Shc in FcεRI-dependent mast cell activation. We showed that p66Shc is expressed in mast cells and that mast cells from p66Shc−/− mice exhibit enhanced responses following Ag stimulation of FcεRI. Furthermore, using RBL-2H3 cell transfectants, we showed that aggregation of FcεRI resulted in the recruitment of a p66Shc–SHIP1 complex to linker for activation of T cells. Collectively, our data identified p66Shc as a negative regulator of mast cell activation.

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p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

Cited by 48 publications

References 38 publications

Mitochondrial protein phosphorylation: instigator or target of lipotoxicity?

Mitochondrial protein phosphorylation: instigator or target of lipotoxicity?

The proapoptotic and antimitogenic protein p66SHC acts as a negative regulator of lymphocyte activation and autoimmunity

p66Shc Is a Negative Regulator of FcεRI-Dependent Signaling in Mast Cells

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