NADH‐cytochrome b5 reductase and cytochrome b5 isoforms as models for the study of post‐translational targeting to the endoplasmic reticulum

Borgese, Nica; D’Arrigo, Antonello; Silvestris, Marcella De; Pietrini, Grazia

doi:10.1016/0014-5793(93)81416-w

Cited by 53 publications

(32 citation statements)

References 51 publications

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“…One additional gene, long-chain fatty acyl elongase, is regulated by SREBPs, although no formal promoter studies have been performed (1). Cytochrome b 5 is a membrane-bound protein that donates electrons to a variety of acceptors that are intermediates in fatty acid desaturation as well as cholesterol biosynthesis (14). The induction of cytochrome b 5 is likely required to maintain the high rates of cholesterol and fatty acid biosynthesis present in livers of SREBP transgenic mice.…”

Section: Resultsmentioning

confidence: 99%

Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes

Horton

Shah

Warrington

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

1,250

1,035

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The synthesis of fatty acids and cholesterol, the building blocks of membranes, is regulated by three membrane-bound transcription factors: sterol regulatory element-binding proteins (SREBP)-1a, -1c, and -2. Their function in liver has been characterized in transgenic mice that overexpress each SREBP isoform and in mice that lack all three nuclear SREBPs as a result of gene knockout of SREBP cleavage-activating protein (SCAP), a protein required for nuclear localization of SREBPs. Here, we use oligonucleotide arrays hybridized with RNA from livers of three lines of mice (transgenic for SREBP-1a, transgenic for SREBP-2, and knockout for SCAP) to identify genes that are likely to be direct targets of SREBPs in liver. A total of 1,003 genes showed statistically significant increased expression in livers of transgenic SREBP-1a mice, 505 increased in livers of transgenic SREBP-2 mice, and 343 showed decreased expression in Scap ؊͞؊ livers. A subset of 33 genes met the stringent combinatorial criteria of induction in both SREBP transgenics and decreased expression in SCAP-deficient mice. Of these 33 genes, 13 were previously identified as direct targets of SREBP action. Of the remaining 20 genes, 13 encode enzymes or carrier proteins involved in cholesterol metabolism, 3 participate in fatty acid metabolism, and 4 have no known connection to lipid metabolism. Through application of stringent combinatorial criteria, the transgenic͞knockout approach allows identification of genes whose activities are likely to be controlled directly by one family of transcription factors, in this case the SREBPs.

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Section: Resultsmentioning

confidence: 99%

Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes

Horton

Shah

Warrington

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

1,250

1,035

View full text Add to dashboard Cite

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“…There are two membrane-bound isoforms of CYB5, the microsomal (CYB5A) and the mitochondrial (CYB5B) isoform, which both derive from two different genes (19,20). CYB5A and CYB5B show high sequence and structural similarities (20,38).…”

Section: Discussionmentioning

confidence: 99%

“…Like the flavoprotein CYB5R, CYB5 can be found as an integral membrane protein in the endoplasmic reticulum and the outer mitochondrial membrane (OMM), as well as a soluble form in erythrocytes (19,20). In contrast to CYB5R, two separate genes encode the different isoforms of CYB5, with CYB5A encoding the microsomal and soluble isoform and CYB5B encoding the mitochondrial isoform.…”

mentioning

confidence: 99%

The Involvement of Mitochondrial Amidoxime Reducing Components 1 and 2 and Mitochondrial Cytochrome b5 in N-Reductive Metabolism in Human Cells

Plitzko

Ott

Reichmann

et al. 2013

Journal of Biological Chemistry

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Background: N-Reduction is catalyzed by a molybdenum-dependent three-component enzyme system. Results: Essential components include mitochondrial but not microsomal cytochrome b 5 , and the mitochondrial amidoxime reducing components 1/2. Conclusion: CYB5 heme is required for activity, and contribution of a particular mARC isoform to N-reduction is dependent on its expression level. Significance: These findings contribute to the understanding of N-reductive pathway in detoxication and drug metabolism.

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“…Proteins of this class do not contain an SS and are delivered to their final destination via post-translational mechanisms (Borgese et al, 1993(Borgese et al, , 2007Kutay et al, 1993). The US9 C-terminal TMD possesses the typical hallmarks of MOM-resident TA proteins, and a mitochondrial localization for US9ADD1-24 and US9ADD1-31 was predicted by two subcellular localization prediction programs.…”

Section: Discussionmentioning

confidence: 99%

Human cytomegalovirus US9 protein contains an N-terminal signal sequence and a C-terminal mitochondrial localization domain, and does not alter cellular sensitivity to apoptosis

Mandic

Miller

Coulter

et al. 2009

Journal of General Virology

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The human cytomegalovirus (CMV) US2-US11 genomic region contains a cluster of genes whose products interfere with antigen presentation by the major histocompatibility complex (MHC) proteins. Although included in this cluster, the US9 gene encodes a glycoprotein that does not affect MHC activity and whose function is still largely uncharacterized. An in silico analysis of the US9 amino-acid sequence uncovered the presence of an N-terminal signal sequence (SS) and a C-terminal transmembrane domain containing the specific hallmarks of known mitochondrial localization sequences (MLS). Expression of full-length US9 and of US9 deletion mutants fused to GFP revealed that the N-terminal SS mediates US9 targeting to the endoplasmic reticulum (ER) and that the C-terminal MLS is both necessary and sufficient to direct US9 to mitochondria in the absence of a functional SS. This dual localization suggested a possible role for US9 in protection from apoptosis triggered by ER-to-mitochondria signalling. Fibroblasts infected with the US2-US11 deletion mutant virus RV798 or with the parental strain AD169varATCC were equally susceptible to death triggered by exposure to tumour necrosis factor (TNF)-a, tunicamycin, thapsigargin, brefeldin A, lonidamine and carbonyl cyanide m-chloro phenyl hydrazone, but were 1.6-fold more sensitive to apoptosis induced by hygromycin B. Expression of US9 in human embryonic kidney 293T cells or in fibroblasts, however, did not protect cells from hygromycin B-mediated death. Together, these results classify US9 as the first CMV-encoded protein to contain an N-terminal SS and a C-terminal MLS, and suggest a completely novel role for this protein during infection. INTRODUCTIONHuman cytomegalovirus (CMV) is a very prevalent betaherpesvirus that poses serious medical concerns in immunocompromised individuals . The ability to evade or modulate host immune responses, coupled with the capacity to establish latency after primary infection, is at the basis of the tremendous success of CMV as a human pathogen.The US2-US11 genomic region has been shown to be dispensable for viral replication in primary human fibroblasts (HF) (Jones & Muzithras, 1992;Kollert-Jons et al., 1991), and to encode five endoplasmic reticulum (ER)-resident glycoproteins, US2, US3, US6, US10 and US11, that disrupt antigen presentation by the major histocompatibility complex (MHC) class I and class II proteins (Lin et al., 2007). Despite sharing some very limited homology with US6, US10 and US11, US9 does not bind to or reduce MHC cell surface levels (Hegde et al., 2002(Hegde et al., , 2006Pereira et al., 1995). US9 was originally described as a member of the US6 family of proteins, which includes the products of the US6-US11 genes. These proteins contain markedly hydrophobic sequences at both the N-and C-termini, and were predicted to insert into cellular membranes (Weston & Barrell, 1986). US9 intracellular localization was initially examined in nonpolarized Madin-Darby canine kidney cells constitutively expressing a C-terminal-tagged ...

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NADH‐cytochrome b₅ reductase and cytochrome b₅ isoforms as models for the study of post‐translational targeting to the endoplasmic reticulum

Cited by 53 publications

References 51 publications

Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes

Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes

The Involvement of Mitochondrial Amidoxime Reducing Components 1 and 2 and Mitochondrial Cytochrome b5 in N-Reductive Metabolism in Human Cells

Human cytomegalovirus US9 protein contains an N-terminal signal sequence and a C-terminal mitochondrial localization domain, and does not alter cellular sensitivity to apoptosis

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