PPIB

PPIB (cyclophilin B) is an endoplasmic reticulum-resident peptidyl-prolyl cis-trans isomerase that functions as a component of a large ER chaperone complex—including BiP, GRP94, PDI, and ERp72—to assist folding of nascent secretory proteins such as immunoglobulin heavy chains and type I procollagen (PMID:12475965, PMID:21282188). Loss-of-function mutations in PPIB cause recessive osteogenesis imperfecta by impairing C-terminal propeptide folding and trimer assembly of pro-α1(I) chains, leading to overmodified procollagen accumulation in the rough ER (PMID:21282188). Beyond its intracellular chaperone role, secreted PPIB binds the cell-surface receptor CD147 to activate ERK signaling and protect against oxidative stress-induced apoptosis in a PPIase activity-dependent manner (PMID:22555451). PPIB also participates in viral replication: it directly binds and stimulates the RNA-binding activity of HCV NS5B polymerase to promote HCV genome replication, and interacts with HIV-1 Gag in a cyclosporin A-sensitive manner (PMID:15989969, PMID:8513493).

1. 1993 High

   The discovery that PPIB physically interacts with HIV-1 Gag polyprotein and capsid p24 in a cyclosporin A-sensitive manner established that cyclophilin B, like cyclophilin A, is a host factor engaged by retroviral structural proteins, raising the question of whether this interaction has functional consequences for viral replication.

   Evidence Yeast two-hybrid screen plus GST-fusion pulldown with cyclosporin A competition in vitro

   PMID:8513493

   Open questions at the time

   • Functional consequence of the Gag–CyPB interaction for HIV-1 replication was not tested
   • Whether CyPB is incorporated into HIV-1 virions like CyPA remains unresolved
   • Structural basis for why CsA disrupts the CyPB–Gag interaction less efficiently than the CyPA–Gag interaction is unknown
2. 2001 Medium

   Demonstration that the Aspergillus niger CypB ortholog possesses intrinsic PPIase activity, localizes to the ER via an N-terminal signal and C-terminal HEEL retention motif, and is upregulated by ER stress confirmed the conserved enzymatic function and ER residency of cyclophilin B across eukaryotes.

   Evidence Recombinant protein PPIase assay, GFP-fusion ER localization, Northern blot after tunicamycin/DTT treatment in A. niger

   PMID:11810224

   Open questions at the time

   • Data are from a fungal ortholog; direct demonstration of human PPIB PPIase activity under ER-stress conditions was not shown here
   • Endogenous substrates of the isomerase in the ER were not identified
3. 2002 High

   Identification of PPIB as a subunit of a large ER multiprotein chaperone complex containing BiP, GRP94, PDI, and other folding factors—associated with unassembled immunoglobulin heavy chains—placed cyclophilin B within the broader ER quality-control machinery rather than as an isolated isomerase.

   Evidence Co-immunoprecipitation, chemical cross-linking, and mass spectrometry in mammalian cells

   PMID:12475965

   Open questions at the time

   • Whether PPIB's PPIase activity is required for complex function or substrate release was not tested
   • Stoichiometry and architecture of the multiprotein complex remain unresolved
   • Specificity of PPIB for particular client proteins beyond Ig heavy chains was not established
4. 2005 High

   Showing that PPIB directly binds HCV NS5B polymerase and stimulates its RNA-binding activity—with RNAi knockdown reducing HCV replication—established PPIB as a proviral host factor exploited by HCV, independent of its ER chaperone role.

   Evidence Co-immunoprecipitation of CyPB–NS5B, in vitro RNA-binding assay, HCV replicon replication after siRNA knockdown

   PMID:15989969

   Open questions at the time

   • Whether the interaction requires PPIB's PPIase catalytic activity or is mediated by a separate binding surface was not resolved
   • Structural basis of the NS5B–CyPB interface is lacking
   • Relevance to other Flaviviridae beyond HCV was not addressed
5. 2011 High

   Patient-derived PPIB-null fibroblasts revealed that cyclophilin B is required for C-terminal propeptide folding and trimer assembly of type I procollagen; its loss causes greater overmodification and ER accumulation than loss of CRTAP or P3H1, positioning PPIB as acting at or upstream of the prolyl 3-hydroxylation complex and establishing recessive PPIB mutations as a cause of osteogenesis imperfecta.

   Evidence Patient fibroblast analysis, SDS-PAGE procollagen mobility, co-IP with PDI/P4H1, comparison with CRTAP- and LEPRE1-deficient cells

   PMID:21282188

   Open questions at the time

   • Whether PPIB directly isomerizes proline residues in the C-propeptide or acts through an alternative mechanism was not distinguished
   • Structural model of the CyPB–procollagen interaction is absent
   • Genotype–phenotype correlation across different PPIB mutations remains limited
6. 2012 Medium

   The finding that secreted PPIB binds CD147 on the cell surface and activates ERK signaling to protect against ROS-induced apoptosis in a PPIase-dependent manner revealed an extracellular signaling function for cyclophilin B distinct from its intraluminal chaperone activity.

   Evidence Co-IP of secreted CyPB with CD147, ERK phosphorylation immunoblot, siRNA knockdown, ROS-induced apoptosis assay in hepatoma cells

   PMID:22555451

   Open questions at the time

   • Independent confirmation of the CyPB–CD147 signaling axis in non-hepatoma cells is lacking
   • How PPIB is actively secreted from the ER (given its KDEL-like retention signal) is unexplained
   • Downstream ERK substrates mediating the cytoprotective effect were not identified

• A unified structural and mechanistic understanding of how PPIB's PPIase activity is partitioned among its distinct client interactions—ER chaperone complex substrates, procollagen C-propeptide folding, HCV NS5B stimulation, and extracellular CD147 signaling—remains an open question.
• No high-resolution structure of PPIB in complex with any endogenous substrate or viral partner has been reported
• Mechanism by which PPIB exits the ER to function extracellularly is unresolved
• Whether PPIB has non-enzymatic scaffolding functions within the ER chaperone complex independent of its isomerase activity is unknown