Cyclophilin A (CyPA) Induces Chemotaxis Independent of Its Peptidylprolyl Cis-Trans Isomerase Activity

Song, Fei; Zhang, Xin; Ren, Xiaobai; Zhu, Ping; Xu, Jing; Wang, Li; Li, Yifei; Zhong, Nan; Ru, Qiang; Zhang, Dawei; Jiang, Jian‐Li; Xia, Bin; Chen, Zhinan

doi:10.1074/jbc.c110.181347

Cited by 67 publications

(63 citation statements)

References 39 publications

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“…CD147 has been shown to function as a signaling receptor for extracellular Cyps A and B and to mediate the chemotactic activity of Cyp toward a variety of immune cells [26,39] Recent in vitro and in vivo studies have demonstrated a role of Cyp-CD147 interactions in the regulation of inflammatory responses in a number of diseases, including acute lung inflammation, rheumatoid arthritis, and cardiovascular disease [30]. While the interaction of CypA with CD147 has been well characterized by NMR, only a few papers have reported the interaction of CypB with CD147 in immune cells [39].…”

Section: Discussionmentioning

confidence: 99%

Release of overexpressed CypB activates ERK signaling through CD147 binding for hepatoma cell resistance to oxidative stress

Kim

Jeong

et al. 2012

Apoptosis

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Cyclophilin, a cytosolic receptor for the immunosuppressive drug cyclosporin A, plays a role in diverse pathophysiologies along with its receptor, CD147. Although the interaction between cyclophilin A and CD147 is well established in inflammatory disease, that of cyclophilin B (CypB) with CD147 has not been fully explored, especially in cancer cell biology, and the exact molecular mechanism underlying such an association is poorly understood. In this study, we first identified high expression levels of CypB in 54 % of hepatocellular carcinoma patient tissues but in only 12.5 % of normal liver tissues. Then, we demonstrated that CypB overexpression protects human hepatoma cells against oxidative stress through its binding to CD147; this protective effect depends on the peptidyl prolyl isomerase activity of CypB. siRNA-mediated knockdown of CypB expression rendered hepatoma cells more vulnerable to ROS-mediated apoptosis. Furthermore, we also determined that a direct interaction between secreted CypB and CD147 regulates the extracellular signal-regulated kinase intracellular signaling pathway and is indispensible for the protective functions of CypB. For the first time, we demonstrated that CypB has an essential function in protecting hepatoma cells against oxidative stress through binding to CD147 and regulating the ERK pathway.

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Section: Discussionmentioning

confidence: 99%

Release of overexpressed CypB activates ERK signaling through CD147 binding for hepatoma cell resistance to oxidative stress

Kim

Jeong

et al. 2012

Apoptosis

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“…Defective stress adaptation of the B. abortus ⌬cypAB mutant is dependent on the PPIase activity. It has been reported that functions assigned to cyclophilins do not always depend on its PPIase activity (44,48,49). To determine if the PPIase activity of B. abortus CypB is required for its physiological role, the amino acid residues Arg 55 and Phe 60 were replaced by alanine (Fig.…”

Section: Resultsmentioning

confidence: 99%

Intracellularly Induced Cyclophilins Play an Important Role in Stress Adaptation and Virulence of Brucella abortus

et al. 2013

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bBrucella is an intracellular bacterial pathogen that causes the worldwide zoonotic disease brucellosis. Brucella virulence relies on its ability to transition to an intracellular lifestyle within host cells. Thus, this pathogen must sense its intracellular localization and then reprogram gene expression for survival within the host cell. A comparative proteomic investigation was performed to identify differentially expressed proteins potentially relevant for Brucella intracellular adaptation. Two proteins identified as cyclophilins (CypA and CypB) were overexpressed in the intracellular environment of the host cell in comparison to laboratorygrown Brucella. To define the potential role of cyclophilins in Brucella virulence, a double-deletion mutant was constructed and its resulting phenotype was characterized. The Brucella abortus ⌬cypAB mutant displayed increased sensitivity to environmental stressors, such as oxidative stress, pH, and detergents. In addition, the B. abortus ⌬cypAB mutant strain had a reduced growth rate at lower temperature, a phenotype associated with defective expression of cyclophilins in other microorganisms. The B. abortus ⌬cypAB mutant also displays reduced virulence in BALB/c mice and defective intracellular survival in HeLa cells. These findings suggest that cyclophilins are important for Brucella virulence and survival in the host cells. C yclophilins (Cyps) are folding helper enzymes that belong to the enzyme class of peptidyl prolyl cis/trans isomerases (PPIases; EC 5.2.1.8). In addition to cyclophilins, PPIases also includes FK506-binding proteins (FKBPs) and parvulins. These three families of proteins that have no sequence or structural homology can be distinguished by being inhibited by the immunosuppressive compounds cyclosporine, FK506, and rapamycin, respectively (1, 2). PPIases catalyze the cis/trans isomerization of peptidyl prolyl bonds. This reaction requires free energy and as a consequence is a slow process at lower temperatures, being the rate-limiting step in protein folding (3). PPIases are thought to be important for the correct folding of nascent proteins as well as their refolding (4-6). It is postulated that conformational isomerization by PPIases controls the activity of target proteins, regulating the interaction with other partner proteins to form complexes (3, 7).Cyclophilins are evolutionary conserved and have been found in all organisms analyzed to date, with the exception of Mycoplasma genitalium and some members of the Archaea (8). They are ubiquitously distributed proteins and like the other PPIases are critical for cell adaptation under stress conditions (9). Cyclophilins have been reported to be involved in several processes, such as adaptation to environmental stress, cell cycle control, signal transduction, and transcriptional regulation (8, 10-12). In addition, they have been implicated in the virulence of fungal and parasitic pathogens (13-17). Recent reports have shown the involvement of PPIases in stress tolerance and pathogenesis of bacteria, su...

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“…CyPA exhibits a wide array of pathophysiological properties, including the induction of inflammatory cell chemotaxis [24,25], the proliferation of VSMC [7,12], and the secretion of matrix metalloproteinases [2,4]. A previous study showed that CyPA is abundantly expressed in atherosclerotic plaque [4].…”

Section: Discussionmentioning

confidence: 99%

Oxidized Low-Density Lipoprotein-Induced Cyclophilin A Secretion Requires ROCK-Dependent Diphosphorylation of Myosin Light Chain

Lin²,

Chen³

et al. 2016

J Vasc Res

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Objective: Accumulation of cyclophilin A (CyPA) within atherosclerotic lesions is thought to be implicated in the progression of atherosclerosis. However, the source of CyPA within atherosclerotic lesions is still unknown. The aim of this study is to determine the role of oxidized low-density lipoproteins (ox-LDL) in vascular smooth muscle cell (VSMC)-derived CyPA secretion and the underlying mechanism. Methods and Results: Abundant CyPA and α-smooth muscle actin (α-SMA) expressed in atherosclerotic lesions was observed in apolipoprotein E-deficient mice. ox-LDL induced CyPA secretion from a primary culture of rat aortic smooth muscle cells in a dose- and time-dependent manner. Sulfosuccinimidyloleate, a CD36 inhibitor, prevented the ox-LDL-induced CyPA secretion. Pre-exposure to either the actin-depolymerizing agent cytochalasin D or the actin-polymerizing agent jasplakinolide inhibited CyPA secretion induced by ox-LDL. Gene silencing of vesicle-associated membrane protein 2 suppressed ox-LDL-induced CyPA secretion. ox-LDL caused the phosphorylation of myosin light chain (MLC). Inhibition of MLC by blebbistatin reversed the secretion of CyPA and the phosphorylation of MLC induced by ox-LDL. MLC kinase inhibitor ML-7 reduced the monophosphorylation of MLC but did not reduce CyPA secretion. Pretreatment with the rho-associated coiled-coil kinase (ROCK) inhibitor Y27632 blocked diphosphorylation of MLC and secretion of CyPA induced by ox-LDL. Conclusions: ox-LDL-induced CyPA secretion requires vesicle transportation, actin remodeling and ROCK-dependent diphosphorylation of MLC. VSMC-derived CyPA induced by ox-LDL may be associated with increased CyPA expression in atherosclerotic lesions.

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Cyclophilin A (CyPA) Induces Chemotaxis Independent of Its Peptidylprolyl Cis-Trans Isomerase Activity

Cited by 67 publications

References 39 publications

Release of overexpressed CypB activates ERK signaling through CD147 binding for hepatoma cell resistance to oxidative stress

Release of overexpressed CypB activates ERK signaling through CD147 binding for hepatoma cell resistance to oxidative stress

Intracellularly Induced Cyclophilins Play an Important Role in Stress Adaptation and Virulence of Brucella abortus

Oxidized Low-Density Lipoprotein-Induced Cyclophilin A Secretion Requires ROCK-Dependent Diphosphorylation of Myosin Light Chain

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