Cathepsin D Triggers Bax Activation, Resulting in Selective Apoptosis-inducing Factor (AIF) Relocation in T Lymphocytes Entering the Early Commitment Phase to Apoptosis

Bidère, Nicolas; Lorenzo, Hans K.; Carmona, Sylvie; Laforge, Mireille; Harper, Francis; Dumont, Céline; Sénik, Anna

doi:10.1074/jbc.m301911200

Cited by 385 publications

(368 citation statements)

References 48 publications

(47 reference statements)

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“…As long as only small amounts of hydrogen peroxide enter lysosomes, the formation of hydroxyl radicals is limited and these probably react with material under degradation, which is the likely (Bidere et al, 2003, Brunk et al, 2001, Castino et al, 2007, Cirman et al, 2004, Guicciardi et al, 2004.…”

Section: The Role Of Lysosomes In Intracellular Iron Metabolismmentioning

confidence: 99%

The role of lysosomes in iron metabolism and recycling

Kurz

Eaton

Brunk

2011

The International Journal of Biochemistry & Cell Biology

167

134

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Iron is the most abundant transition metal in the earths crust. It cycles easily between ferric (oxidized; Fe(III)) and ferrous (reduced; Fe(II)) and readily forms complexes with oxygen, making this metal a central player in respiration and related redox processes. However, loose iron, not within heme or iron-sulfur cluster proteins, can be destructively redox-active, causing damage to almost all cellular components, killing both cells and organisms. This may explain why iron is so carefully handled by aerobic organisms. Iron uptake from the environment is carefully limited and carried out by specialized iron transport mechanisms. One reason that iron uptake is tightly controlled is that most organisms and cells cannot efficiently excrete excess iron. When even small amounts of intracellular free iron occur, most of it is safely stored in a non-redox-active form in ferritins. Within nucleated cells, iron is constantly being recycled from aged iron-rich organelles such as mitochondria and used for construction of new organelles. Much of this recycling occurs within the lysosome, an acidic digestive organelle. Because of this, most lysosomes contain relatively large amounts of redox-active iron and are therefore unusually susceptible to oxidant-mediated destabilization or rupture. In many cell types, iron transit through the lysosomal compartment can be remarkably brisk. However, conditions adversely affecting lysosomal iron handling (or oxidant stress) can contribute to a variety of acute and chronic diseases. These considerations make normal and abnormal lysosomal handling of iron central to the understanding and, perhaps, therapy of a wide range of diseases

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Section: The Role Of Lysosomes In Intracellular Iron Metabolismmentioning

confidence: 99%

The role of lysosomes in iron metabolism and recycling

Kurz

Eaton

Brunk

2011

The International Journal of Biochemistry & Cell Biology

167

134

View full text Add to dashboard Cite

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“…Interestingly, our findings provide new evidence that LRP1 RIP may be also modulated via a paracrine loop. The pro-cath-D secreted by cancer cells may influence the tumor Human cath-D siRNA (target sequence 5 0 -AAGCUGGUGGACCAGAA-CAUC-3 0 , residues 666-684) was described previously (Bidere et al, 2003). COS cells were transfected with pFR-Luc and CMV-b-gal with or without LRP1-GV, and plus or minus DAPT (20 mM) for 24 h (panel d).…”

Section: Ectopic Cath-d and Pro-cath-d Inhibit Lrp1 Rip In Cos Cells mentioning

confidence: 99%

Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

et al. 2011

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The aspartic protease cathepsin-D (cath-D) is a marker of poor prognosis in breast cancer that is overexpressed and hypersecreted by human breast cancer cells. Secreted procath-D binds to the extracellular domain of the b-chain of the LDL receptor-related protein-1 (LRP1) in fibroblasts. The LRP1 receptor has an 85-kDa transmembrane b-chain and a noncovalently attached 515-kDa extracellular a-chain. LRP1 acts by (1) internalizing many ligands via its a-chain, (2) activating signaling pathways by phosphorylating the LRP1b-chain tyrosine and (3) modulating gene transcription by regulated intramembrane proteolysis (RIP) of its b-chain. LRP1 RIP involves two cleavages: the first liberates the LRP1 ectodomain to give a membrane-associated form, LRP1b-CTF, and the second generates the LRP1b-intracellular domain, LRP1b-ICD, that modulates gene transcription. Here, we investigated the endocytosis of pro-cath-D by LRP1 and the effect of pro-cath-D/LRP1b interaction on LRP1b tyrosine phosphorylation and/or LRP1b RIP. Our results indicate that pro-cath-D was partially endocytosed by LRP1 in fibroblasts. However, pro-cath-D and ectopic cath-D did not stimulate phosphorylation of the LRP1b-chain tyrosine. Interestingly, ectopic cath-D and its catalytically inactive D231N cath-D, and pro-D231N cath-D all significantly inhibited LRP1 RIP by preventing LRP1b-CTF production. Thus, cath-D inhibits LRP1 RIP independently of its catalytic activity by blocking the first cleavage. As cath-D triggers fibroblast outgrowth by LRP1, we propose that cath-D modulates the growth of fibroblasts by inhibiting LRP1 RIP in the breast tumor microenvironment.

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“…Apaf-1 or caspase-9) do not influence the mitochondrionuclear translocation of AIF have been reported for numerous in vitro cell death models (Table 1b). Moreover, in some models, the release of AIF clearly occurs independently from that of cytochrome c, for example, in the early apoptosis of primary T cells induced by staurosporine 36,37 or in human embryonic fibroblasts infected by herpes simplex virus-1. 38 Altogether these data suggest a different scheme from that evoked above.…”

Section: Caspase-independent Aif Release From Mitochondriamentioning

confidence: 99%