Induction of necrotic cell death and mitochondrial permeabilization by heme binding protein 2/SOUL

Szigeti, András; Bellyei, Szabolcs; Gasz, Balázs; Boronkai, Árpád; Hocsák, Enikö; Minik, Orsolya; Bognár, Zita; Varbiro, Gabor; Sümegi, Balázs; Gallyas, Ferenc

doi:10.1016/j.febslet.2006.10.067

Cited by 42 publications

(40 citation statements)

References 30 publications

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“…However, very little information is available about their other biological functions. Previously, we reported that SOUL can facilitate cell death in taxol-and A23187-treated cells (1). Analyzing the protein sequence data base, we found that SOUL contained a sequence with a high similarity to BH3 domains (Fig.…”

Section: Discussionmentioning

confidence: 73%

“…To detect SOUL protein in different types of tissues, we developed anti-SOUL, as was described earlier (1). Using the purified anti-SOUL antibody, different levels of SOUL expression were identified in human tissue samples, and it could be detected in some malignant tissues too (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously observed that heme-binding protein 2/SOUL facilitates mitochondrial permeability transition and cell death without affecting reactive oxygen production (1). A data base search indicated that heme-binding protein 2/SOUL has a BH3 2 domain-like structure.…”

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confidence: 99%

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Facilitation of Mitochondrial Outer and Inner Membrane Permeabilization and Cell Death in Oxidative Stress by a Novel Bcl-2 Homology 3 Domain Protein

Szigeti

Hocsák

Rapolti

et al. 2010

Journal of Biological Chemistry

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We identified a sequence homologous to the Bcl-2 homology 3 (BH3) domain of Bcl-2 proteins in SOUL. Tissues expressed the protein to different extents. It was predominantly located in the cytoplasm, although a fraction of SOUL was associated with the mitochondria that increased upon oxidative stress. Recombinant SOUL protein facilitated mitochondrial permeability transition and collapse of mitochondrial membrane potential (MMP) and facilitated the release of proapoptotic mitochondrial intermembrane proteins (PMIP) at low calcium and phosphate concentrations in a cyclosporine A-dependent manner in vitro in isolated mitochondria. Suppression of endogenous SOUL by diced small interfering RNA in HeLa cells increased their viability in oxidative stress. Overexpression of SOUL in NIH3T3 cells promoted hydrogen peroxide-induced cell death and stimulated the release of PMIP but did not enhance caspase-3 activation. Despite the release of PMIP, SOUL facilitated predominantly necrotic cell death, as revealed by annexin V and propidium iodide staining. This necrotic death could be the result of SOUL-facilitated collapse of MMP demonstrated by JC-1 fluorescence. Deletion of the putative BH3 domain sequence prevented all of these effects of SOUL. Suppression of cyclophilin D prevented these effects too, indicating that SOUL facilitated mitochondrial permeability transition in vivo. Overexpression of Bcl-2 and Bcl-x L , which can counteract the mitochondriapermeabilizing effect of BH3 domain proteins, also prevented SOUL-facilitated collapse of MMP and cell death. These data indicate that SOUL can be a novel member of the BH3 domain-only proteins that cannot induce cell death alone but can facilitate both outer and inner mitochondrial membrane permeabilization and predominantly necrotic cell death in oxidative stress.We have previously observed that heme-binding protein 2/SOUL facilitates mitochondrial permeability transition and cell death without affecting reactive oxygen production (1). A data base search indicated that heme-binding protein 2/SOUL has a BH3 2 domain-like structure. BH3 domain-only proteins play a significant role in the processes of cell death and survival (2, 3). Mammalian cells express a group of evolutionarily conserved proteins known as the Bcl-2 (B-cell-associated leukemia protein 2) family. The effect of Bcl-2 proteins on the apoptotic process is due to the presence of one or more conserved regions of amino acid sequences, known as Bcl-2 homology (BH) domains. Based on their function, Bcl-2 proteins can have either proapoptotic (Bax, Bad, Bak, Bim, and Bid) or antiapoptotic (Bcl-2 and Bcl-x L ) properties. All antiapoptotic Bcl-2-related proteins described to date contain BH1, BH2, and sometimes BH4 domains in addition to the BH3 domain (4 -6). Proapoptotic family members either share the multidomain structure (e.g. Bax and Bak) or contain only the BH3 domain (e.g. Bim and Bid). Bcl-2 proteins containing only the BH3 domain have been suggested to play an important role in initiating mitochondrial-med...

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Section: Discussionmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

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Facilitation of Mitochondrial Outer and Inner Membrane Permeabilization and Cell Death in Oxidative Stress by a Novel Bcl-2 Homology 3 Domain Protein

Szigeti

Hocsák

Rapolti

et al. 2010

Journal of Biological Chemistry

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“…HEBP2 could exaggerate the dissipation of the mitochondrial membrane potential and induce necrosis in concert with calcium (26). This suggested its involvement in intracellular calcium signaling, a process in which ALG-2 is definitely involved as an EF-hand protein.…”

Section: Figure 10 Knockdown Of Endogenous Alg-2 Expression In Hela mentioning

confidence: 99%

“…HEBP2 is highly expressed in the retina and pineal gland (25) and shares 40% sequence similarity with p22 HBP (HEBP1), a ubiquitously expressed heme-binding protein. It has been suggested that HEBP2 plays roles in mitochondrion-mediated cell death (26), which might be related to its ability to interact with the antiapoptotic proteins Bcl-2/Bcl-xl through a BH3-like motif (27,28). Unlike p22 HBP , the ability of HEBP2 to bind heme is controversial, and its roles in heme-related activities, such as the generation of reactive oxygen species, are poorly defined.…”

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confidence: 99%

Structural and Functional Study of Apoptosis-linked Gene-2·Heme-binding Protein 2 Interactions in HIV-1 Production

Zhang²,

Feng

et al. 2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerIn the HIV-1 replication cycle, the endosomal sorting complex required for transport (ESCRT) machinery promotes viral budding and release in the late stages. In this process, the ESCRT proteins, ALIX and TSG101, are recruited through interactions with HIV-1 Gag p6. ALG-2, also known as PDCD6, interacts with both ALIX and TSG101 and bridges ESCRT-III and ESCRT-I. In this study, we show that ALG-2 affects HIV-1 production negatively at both the exogenous and endogenous levels. Through a yeast two-hybrid screen, we identified HEBP2 as the binding partner of ALG-2, and we solved the crystal structure of the ALG-2⅐HEBP2 complex. The function of ALG-2⅐HEBP2 complex in HIV-1 replication was further explored. ALG-2 inhibits HIV-1 production by affecting Gag expression and distribution, and HEBP2 might aid this process by tethering ALG-2 in the cytoplasm.The endosomal sorting complex required for transport (ESCRT) 3 machinery functions in HIV-1 budding and release in the late stages of viral replication (1-3). In this process, ALIX (ALG-2 interacting protein X) and TSG101 (tumor susceptibility gene 101), components of ESCRT-III and ESCRT-I, are recruited to the budding site of HIV-1 through interactions with HIV-1 Gag p6 (4 -8). This promotes the release of virion particles (9) with the help of AAA-ATPase VPS4B (vacuolar protein sorting 4 homolog B) (10, 11). The penta-EF-hand protein ALG-2 (apoptosis-linked gene-2, also known as PDCD6) participates in the process by interacting with both ALIX (12, 13) and TSG101 (14) in a calcium-dependent manner and bridges ESCRT-III and ESCRT-I through dimerization (15)(16)(17). However, the function of ALG-2 in viral replication, especially that of HIV-1, remains unknown.ALG-2 was first identified in a functional screen for anti-apoptotic proteins involved in T-cell receptor, Fas, and glucocorticoid-induced cell death (18). It was defined as a proapoptotic molecule because expression of its antisense strand led to rescue from cell death (19). However, ALG-2 knock-out mice are viable and exhibit normal T-cell development (20), which suggested that other redundant proteins might exist in mammalian cells. ALG-2 is a penta-EF-hand protein (13, 15), containing five repeats of the EF-hand motif, and coordinates three calcium ions via EF1, EF3, and EF5. However, the coordination of calcium by EF5 is weak and may be physiologically unimportant. ALG-2 exists as a dimer, which might be critical for its function as an adaptor molecule in signal transduction (15). ALG-2 can interact with dozens of proteins through several pockets (pockets 1-3) on its molecular surface. The binding motif for ALG-2, designated as the ALG-2-binding site (ABS), is a short sequence rich in Pro, Gly, and Tyr. Two typical ABS sequences have been described. ABS-1, which is represented as PPYPXXPGYP (X represents any residue) and occupies pocket 1 on the ALG-2 surface, is found in ALIX and PLSCR3 (6), whereas ABS-2, containing a PXPGF sequence that binds pocket 3, is found in SEC31 and PLSCR3 (1...

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Determination of Hemin‐Binding Characteristics of Proteins by a Combinatorial Peptide Library Approach

et al. 2011

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Studies of the binding of heme/hemin to proteins or peptides have recently intensified as it became evident that heme serves not only as a prosthetic group, but also as a regulator and effector molecule interacting with transmembrane and cytoplasmic proteins. The iron-ion-containing heme group can associate with these proteins in different ways, with the amino acids Cys, His, and Tyr allowing individual modes of binding. Strong coordinate-covalent binding, such as in cytochrome c, is known, and reversible attachment is also discussed. Ligands for both types of binding have been reported independently, though sometimes with different affinities for similar sequences. We applied a combinatorial approach using the library (X)(4) (C/H/Y)(X)(4) to characterize peptide ligands with considerable hemin binding capacities. Some of the library-selected peptides were comparable in terms of hemin association independently of whether or not a cysteine residue was present in the sequence. Indeed, a preference for His-based (≈39 %) and Tyr-based (≈40 %) sequences over Cys-based ones (≈21 %) was detected. The binding affinities for the library-selected peptides, as determined by UV/Vis spectroscopy, were in the nanomolar range. Moreover, selected representatives efficiently competed for hemin binding with the human BK channel hSlo1, which is known to be regulated by heme through binding to its heme-binding domain.

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Induction of necrotic cell death and mitochondrial permeabilization by heme binding protein 2/SOUL

Cited by 42 publications

References 30 publications

Facilitation of Mitochondrial Outer and Inner Membrane Permeabilization and Cell Death in Oxidative Stress by a Novel Bcl-2 Homology 3 Domain Protein

Facilitation of Mitochondrial Outer and Inner Membrane Permeabilization and Cell Death in Oxidative Stress by a Novel Bcl-2 Homology 3 Domain Protein

Structural and Functional Study of Apoptosis-linked Gene-2·Heme-binding Protein 2 Interactions in HIV-1 Production

Determination of Hemin‐Binding Characteristics of Proteins by a Combinatorial Peptide Library Approach

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