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, To reconstitute Bclx-silenced BT549 cells with our BclxL constructs, shRNA-BclxL-expressing cells were transfected by electroporation with pcDNA3 vector encoding BclxL-WT, BclxL-Acta (MT) or BclxL-CytB5 (ER) or empty vector. Twenty-four hours after transfection, cells were placed in a medium supplemented with 0.6 mg/ml of neomycin. Neomycin-resistant colonies were isolated using cloning cylinders, Then, cells stably expressing shRNA were selected for 7 days using 0.5 ?g/ml of puromycin

P. Antibodies and . Reagents, Anti-BclxL, anti-Bcl-2, anti-Akt, anti-phosphoS473 Akt, anti-phosphoThr308 Akt, and anti-BAD were from, Anti-CD95 (C20), anti-VDAC1, and Ru360 were purchased from Santa Cruz

, These peptides were coupled with the cell-permeant sequence of antennapedia homeodomain (RQIKIWFQNRRMKWKK) to their C-terminal domain. IgCD95L and metalloprotease-cleaved CD95L were generated in the laboratory, N-terminal peptide (LGKSARDVFTKGYGFG) and L14-15 peptide, vol.12

, FuraPE3 and Fluo2-AM were from Euromedex

;. and B. Sigma, GFP sequence lacking stop codon was amplified by PCR from pEGFPN1 sequence using primer pair: sense CGGGATCCATGGTGAGCAAGGGCGAGGAG CTG and antisense CCGCTCGAGCTTGTACAGCTCGTCCATGCCG. The amplicons was digested by Xho1 and BamH1 and inserted into Xho1 and BamH1-cleaved pcDNA3.1(+). Next, pcDNA3.1(+)-GFP was linearized using XhoI/XbaI and sequences corresponding to amino acid residues 107-142 of human CytB5 (ITTIDSSSSWWTNWVIPAISAVAVALMYRLYMAED) or residues 613-639 of Acta, mitotracker green and Rhod2-AM were from Life Technologies SAS

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, Calcium Release-Activated Calcium channels. ER, Endoplasmic Reticulum. IP 3 , Inositol 1,4,5-tris-Phosphate. IP 3 R, IP 3 Receptors. MCU, Mitochondrial Calcium Uniporter. PLC, PhosphoLipase C. PTP, Permeability Transition Pore. SERCA, Sarcoplasmic/Endoplasmic Reticulum Ca 2+ -ATPase, CRAC channels

. Soce, Store-Operated Calcium Entry. SSRI, Selective Serotonin Re-uptake Inhibitor

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A. Reagents, 000) was purchased from Thermo Fisher Scientific. Antibody against PDI (ADI-SPA-890, dilution 1:1,000) was obtained from Enzo Life Sciences. The secondary antibodies anti-mouse (#7076, dilution 1:1,000) and anti-rabbit (#7074, dilution 1:1,000) were obtained from Cell Signaling Technology, phospho-S6K(T389) (#9205, dilution 1:1,000), 4EBP1 (#9452, dilution 1:1,000), phospho-4EBP1(T37/46) (#2855, dilution 1:1,000), AKT (#4691, dilution 1:1,000), phospho-AKT(Ser473) (#4060, dilution 1:1,000), p62 (#5114, dilution 1:1,000), LC3 AB (#12741, dilution 1:1,000), b-actin (#4967, dilution 1:1,000), RAPTOR (#2280, dilution 1:1,000), p.6

, HA-p62 plasmid was a gift from Qing Zhong (Addgene plasmid #28027)

, Except for JURKAT (RPMI GIBCO), all the cells lines were grown in DMEM high glucose (4.5 g l À 1 ) (GIBCO) supplemented with 10% of fetal bovine serum (Dominique Dutscher), glutamine (2 mM), penicillin (Sigma, 100 U ml À 1 ) and streptomycin (Sigma, 100 mg ml À 1 ), at 37°C, 5% CO 2 in humidified atmosphere. Mycoplasma contamination check was carried out using the VenorGeM Kit, Cell culture. U2OS, HEK293A, A549 and JURKAT cells were obtained from ATTC. WT and ATG5 À / À MEFs were kindly provided by Patricia Boya

, The activation of glutaminolysis was performed by adding glutamine (2 mM final concentration) and leucine (0.8 mM final concentration). When indicated, DMKG was added to a final concentration of 0.2-2 mM. The different inhibitors were used concomitantly with the activation of glutaminolysis as follows: DON (40 mM), BPTES (30 mM)

S. Plasmids and . Transfections, The plasmid transfections were carried out using Jetpei (Polyplus Transfection) according to the manufacturer's instructions. Briefly, 70% confluent cells were transfected with 2-3 mg of plasmid. Twenty-four hours later cells were starved in the presence or absence of LQ for 48 h more. siRNA transfections were performed using Interferin@ (Polyplus Transfection) according to the manufacturer's instructions: cells at 50% of confluence were transfected with siRNA (final concentration 10 nM) in complete medium for 48 h and then starved with different treatments for another 72 h. All siRNAs were obtained from Dharmacon (on-target plus smartpool siRNA)

, UGGUUUACAUGUUGUGUGA, issue.3

, UGGUUUACAUGUUUUCCUA

, UGGGCUGGAUCCAAGACCA, GUGCGGA ACUGAUCAGAA, issue.1

, ACAAAGAUGUGCUUCGAGA, GGACCCAUCUGUCUU CAAA, vol.62, issue.4

. Raptor,

, CACGGAAGAUGUUCGACAA, issue.3

, UGGAGAAGCGUGUCAGAUA

;. Rictor and . Gcacuucgauua,

, GLS

, CCUGAAGCAGUUCGAAAUA, issue.2

, AGAAAGUGGAGAUCGAAAU, issue.4

, After the respective treatments cells were washed two times with phosphate-buffered saline (PBS) and lysed with RIPA buffer containing a cocktail of protease inhibitor (P8340 Sigma), inhibitors of phosphatases (P0044 and P5726 Sigma) and PMSF 1 mM. Protein quantification was performed using BCA kit (Pierce), Immunoblots. 5 Â 10 6 JURKAT cells or 2 Â 10 6 U2OS, A549, HEK293 cells were seeded in 10 cm plates

, After two washes with cold PBS, cells were lysed with lP lysis buffer (40 mM Hepes pH 7.5, 120 mM NaCl, 1 mM EDTA, 0.3% CHAPS, protease inhibitor cocktail P8340 Sigma and 1 mM PMSF). Protein extracts were incubated overnight at 4°C with anti-HA magnetic beads, Thereafter beads were washed twice with cold PBS and eluted with Laemmli buffer for immunoblot analysis

, HEK293A, JURKAT) and the number of viable cells was determined after 24-144 h, using the TC20 Automated Cell Counter (Bio-Rad) according to the manufacturer's protocol. Briefly, after the respective treatments cells were detached with trypsin/EDTA and 10 ml of the cells suspension were mixed with 10 ml trypan blue 5% solution (Bio-Rad) and analysed with the TC20 cell counter (Bio-rad). To estimate the percentage of cell death, Cell proliferation and cell viability. 1.2 Â 10 5 cells were seeded for all the cell lines (U2OS, A549

. Real-time-pcr, The mRNAs from cells were isolated using Trisol (Invitrogen)

, One microgram of total mRNA was reverse transcribed using GoScript Reverse Transcription System (Promega), Specific primers for BAX

, Subcellular fractionation. 25 Â 10 6 cells were seeded in two 25 cm plates for each condition and after the respective treatment the cells were subjected to a subcellular fractionation using the Cell Fractionation Kit (#9038) of Cell Signaling Technology, following the manufacturer's recommendations. Flow cytometry. After treatment, cells were stained with annexin V and propidium iodide (PI) (Annexin V-early apoptosis detection kit, #6592 Cell Signaling Technology) following the manufacturer's instructions. Then, cells were analysed using BDFACS Canto BD-Biosciences flow cytometer

, For the co-localization experiments, after the fixation, cells were permeabilized using Triton-X 0.05% during 10 min, and then blocked with BSA 5% in PBS for 30 min. Finally, cells were incubated with the primary antibodies for 1 h at 37°C. After three washes with PBS, the cover slide was incubated for 1 h at 37°C with the appropriate secondary antibody (anti-rabbit Alexa488, dilution 1:400 or anti-mouse Alexa555, Confocal microscopy. 1.2 Â 10 5 cells were grown in coverslips with the respective treatments for 72 h

, À 1 ) with or without leucine/glutamine or DMKG during 72 h for U2OS and A549, and during 144 h for HEK293A. Similarly, U2OS cells were starved for amino acids, treated with LQ, RAP (100 nM) and/or 3MA (5 mM) as indicated for 72 h. After the treatment, 1.5 Â 10 3 cells (U2OS, A549) or 3 Â 10 4 (HEK293A) were seeded in a 3 cm plate containing complete media. After 14 days cells were fixed with paraformaldehyde 4% in PBS (30 min) and stained with violet crystal 5% for 15 min, Then, the plates were washed with water and imaged using ChemiDoc MP Imager

, Dehydration was performed with ethanol (50%, 70%, 95% and absolute ethanol). Thereafter, the samples were embedded in Epon/Ethanol and evaporated overnight at room temperature. The samples were processed for ultra-microtomy according to standard procedures. Finally sample imaging was performed using a Hitachi H7650 microscope operated at À 80 KV with a camera Gatan-11 MPx, After the respective treatment, cells were fixed for 1 h at 4°C in 4% paraformaldehyde in PBS, washed and fixed again 1 h at room temperature in aqueous 2% osmium tetroxide in 0.2 M sodium cacodylate

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