PPIB

PPIB encodes cyclophilin B (CypB), a peptidyl-prolyl cis/trans isomerase synthesized with a hydrophobic leader sequence that targets it to the secretory pathway, with PPIase activity that is inhibited by cyclosporin A (PMID:2040592). Within the rough endoplasmic reticulum, CypB assembles with CRTAP and prolyl 3-hydroxylase 1 (P3H1/LEPRE1) into a complex that 3-hydroxylates Pro986 in the α1 chains of type I collagen (PMID:19781681). CypB is the earliest-acting component of this collagen-folding machinery: it is required for efficient folding of the procollagen C-terminal propeptide and for pro-α chain trimerization, and its loss causes slow trimer assembly, accumulation of overmodified procollagen in the RER, and aberrant association of procollagen with PDI and prolyl 4-hydroxylase 1 (PMID:21282188). Loss-of-function PPIB mutations cause autosomal-recessive osteogenesis imperfecta (PMID:19781681). Beyond its intracellular role, secreted CypB binds the cell-surface receptor CD147 to activate ERK signaling and protect cells from oxidative stress-induced apoptosis in a manner dependent on its PPIase activity (PMID:22555451).

1. 1991 High

   Established that PPIB encodes a distinct, secreted cyclophilin with bona fide enzymatic PPIase activity, defining it as a secretory-pathway isomerase rather than a cytosolic one.

   Evidence Protein purification from human milk, cDNA cloning, recombinant expression, PPIase and cyclosporin A inhibition assays

   PMID:2040592

   Open questions at the time

   • Physiological substrates of the PPIase activity not identified
   • Subcellular site of action within the secretory pathway not resolved
   • No link to a biological process established yet
2. 2009 High

   Connected CypB to collagen biosynthesis by placing it in a CRTAP/P3H1 complex that 3-hydroxylates Pro986 of type I collagen and showing its loss causes recessive osteogenesis imperfecta.

   Evidence Human genetic analysis of OI families plus biochemical quantification of collagen 3-prolyl hydroxylation in patient cells, compared to CRTAP/LEPRE1 deficiency

   PMID:19781681

   Open questions at the time

   • Why hydroxylation is less reduced than in CRTAP/LEPRE1 deficiency not fully explained
   • Whether the isomerase contributes a function independent of hydroxylation not directly tested here
3. 2011 High

   Resolved CypB's order of action, showing it is the earliest-required factor for procollagen C-propeptide folding and pro-α chain trimerization, upstream of hydroxylation.

   Evidence Pulse-chase trimer assembly, co-IP of procollagen with PDI/P4H1, and cell fractionation in PPIB-deficient patient fibroblasts versus CRTAP/LEPRE1 deficiency

   PMID:21282188

   Open questions at the time

   • Direct enzymatic substrate prolines isomerized by CypB during folding not mapped
   • Structural basis of complex assembly not determined
4. 2012 Medium

   Identified an extracellular signaling role for secreted CypB via CD147, linking its PPIase activity to ERK activation and oxidative stress survival.

   Evidence siRNA knockdown, co-IP of secreted CypB with CD147, ERK phosphorylation and apoptosis assays under oxidative stress in hepatoma cells

   PMID:22555451

   Open questions at the time

   • Single-lab study using overexpression; physiological relevance of secreted CypB at endogenous levels unclear
   • Mechanism by which PPIase activity is required for CD147-ERK signaling not defined
   • No reciprocal validation across cell types

• How CypB's isomerase activity mechanistically drives procollagen folding versus its scaffolding role in the hydroxylation complex, and whether its extracellular CD147 signaling occurs under normal physiology, remain unresolved.
• No structure of the CypB/CRTAP/P3H1 complex
• Substrate prolines isomerized during procollagen folding unmapped
• Endogenous relevance of secreted CypB-CD147 axis untested in vivo