Cyclophilin‐A is a zinc‐dependent DNA binding protein in macrophages

Krummrei, Ulrike; Bang, Renate; Schmidtchen, Robert; Brune, Kay; Bang, Holger

doi:10.1016/0014-5793(95)00815-q

Cited by 45 publications

(34 citation statements)

References 33 publications

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“…There was no reaction of SLA with mAb 7F1. The mAb 7F1 is highly specific for CypA from mammalian cells and therefore a contamination with rabbit blood cells from the culture system can be excluded (Krummrei et al, 1995). In contrast, three proteins from SLA with apparent molecular masses (MM) of 19, 20 and 22 kDa cross-reacted with the polyclonal antibodies against CypB (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This phenomenon may have several explanations. First, data from ourselves and others (Bergsma et al, 1991;Krummrei et al, 1995) revealed the presence of other cyclophilin isoforms in MP, rendering it possible that additional deprivation of these cyclophilins would further enhance the antileishmanial activity. However, our attempts to reduce further the expression of other cyclophilins (CypC) proved increasingly lethal for MP (data not shown).…”

Section: Discussionmentioning

confidence: 96%

“…represent such a target structure, we blocked the expression of the major cyclophilin isoform in MP, i.e. cyclophilin A (CypA) (Krummrei et al, 1995), using antisense PON. The PON had been designed on the basis of the known sequence of the murine CypA, corresponding to the N-terminus immediately downstream from the initiation codon; the corresponding sense PON was used as a control.…”

Section: Majormentioning

confidence: 99%

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Host‐cell cyclophilin is important for the intracellular replication of Leishmania major

Hoerauf

Rascher

Bang

et al. 1997

Molecular Microbiology

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SummaryThe antiparasitic effects of cyclosporin A were examined in leishmanial infection by analysing the role of CsA-binding proteins (cyclophilins) in the host-parasite interaction. We hypothesized that the leishmanicidal effects of CsA on Leishmania major infected macrophages might be mediated through a cyclophilin of either the parasite or the host cell. Two cyclophilins (20 and 22 kDa) were purified from L. major parasites and N-terminally sequenced. Although enzyme activity of these cyclophilins was inhibited by CsA, pretreatment of L. major parasites with CsA did not result in reduction of a subsequent macrophage infection, arguing against a role of L. major cyclophilins as infectivity potentiators. However, host-cell cyclophilin A (CypA) was found to be critically involved in the intracellular replication of L. major parasites in murine macrophages. An antisense oligonucleotide to murine CypA was constructed and added to cultures of peritoneal macrophages prior to infection with L. major parasites. This treatment strongly reduced the expression of CypA in macrophages and resulted in the inhibition of the intracellular replication of L. major amastigotes. These data indicate that interaction of amastigotes with host-cell cyclophilin is an important part of the intracellular replication machinery of L. major and define, for the first time, a direct involvement of a cyclophilin in the survival strategies of an intracellular parasite.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Majormentioning

confidence: 99%

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Host‐cell cyclophilin is important for the intracellular replication of Leishmania major

Hoerauf

Rascher

Bang

et al. 1997

Molecular Microbiology

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“…Samples were incubated for 5 h at room temperature with gentle rotation. Studies in our laboratory have shown that HeLa nuclei incubated under these conditions undergo very little spontaneous chromatin degradation (41).…”

Section: Methodsmentioning

confidence: 99%

Native Recombinant Cyclophilins A, B, and C Degrade DNA Independently of Peptidylprolyl cis-trans-Isomerase Activity

Montague

Hughes

Cidlowski

1997

Journal of Biological Chemistry

163

122

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Previous work in our laboratory (Montague, J., Gaido, M., Frye, C., and Cidlowski, J. (1994) J. Biol. Chem. 269, 18877-18880) has shown that human recombinant cyclophilins A, B, and C have sequence homology with the apoptotic nuclease NUC18 and that denatured cyclophilins can degrade DNA. We have now evaluated the nucleolytic activity of recombinant cyclophilins under native conditions. We show that nuclease activity inherent to cyclophilins is distinct from cis-trans-peptidylprolyl isomerase activity and is similar to that described for apoptotic nucleases. Cyclophilin nucleolytic activity is stimulated by Ca 2؉ and/or Mg 2؉, with a combination of the two being optimal for cyclophilins A and B. Mg 2؉ alone is sufficient for cyclophilin C nuclease activity. pH optimums are in the range of pH 7.5-9.5. Cyclophilins can degrade both single-stranded and double-stranded DNA. Additionally, cyclophilins produce 3-OH termini in linear double-stranded substrates, suggesting the cuts produced are similar to those of apoptotic cells. Cyclophilins also display endonucleolytic activity, demonstrated by their ability to degrade supercoiled DNA. In the absence of ions, cyclophilins bind linearized DNA. When added to nuclei from nonapoptotic cells, cyclophilin C induces 50-kilobase pair DNA fragmentation but not internucleosomal fragmentation. Together, these data suggest that cyclophilins are involved in degradation of the genome during apoptosis.

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“…It is possible that both Roc1 and CypA, like their mammalian homologs, are present in both the cytosol and the nucleus of Arabidopsis. CyPs also function as DNA binding proteins (50) and have been implicated in the regulation of apoptosis because of their nuclease activity, which is independent of their PPIase activity (49). Integration of the T-DNA involves illegitimate recombination in plants which usually includes small deletions of the plant DNA at target sites (51), suggesting that a nuclease function is needed for T-DNA integration into the plant genome.…”

Section: Discussionmentioning

confidence: 99%

Agrobacterium VirD2 protein interacts with plant host cyclophilins

Deng

Chen

Wood

et al. 1998

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

101

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Agrobacterium tumefaciens induces crown gall tumors on plants by transferring a nucleoprotein complex, the T-complex, from the bacterium to the plant cell. The Tcomplex consists of T-DNA, a single-stranded DNA segment of the tumor-inducing plasmid, VirD2, an endonuclease covalently bound to the 5 end of the T-DNA, and perhaps VirE2, a single-stranded DNA binding protein. The yeast two-hybrid system was used to screen for proteins interacting with VirD2 and VirE2 to identify components in Arabidopsis thaliana that interact with the T-complex. Three VirD2-and two VirE2-interacting proteins were identified. Here we characterize the interactions of VirD2 with two isoforms of Arabidopsis cyclophilins identified by using this analysis. The VirD2 domain interacting with the cyclophilins is distinct from the endonuclease, omega, and the nuclear localization signal domains. The VirD2-cyclophilin interaction is disrupted in vitro by cyclosporin A, which also inhibits Agrobacterium-mediated transformation of Arabidopsis and tobacco. These data strongly suggest that host cyclophilins play a role in T-DNA transfer.

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Cyclophilin‐A is a zinc‐dependent DNA binding protein in macrophages

Cited by 45 publications

References 33 publications

Host‐cell cyclophilin is important for the intracellular replication of Leishmania major

Host‐cell cyclophilin is important for the intracellular replication of Leishmania major

Native Recombinant Cyclophilins A, B, and C Degrade DNA Independently of Peptidylprolyl cis-trans-Isomerase Activity

Agrobacterium VirD2 protein interacts with plant host cyclophilins

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