KLKB1

KLKB1 encodes plasma prekallikrein, the zymogen of plasma kallikrein, a serine protease that operates at the interface of the kinin, renin-angiotensin, and coagulation systems (PMID:26969407, PMID:38294975). In vivo CRISPR-Cas9 disruption of KLKB1 in humans produces dose-dependent loss of plasma kallikrein protein and prevents hereditary angioedema attacks, establishing that KLKB1 expression directly sets circulating kallikrein levels (PMID:38294975). Catalytically, plasma kallikrein cleaves pro-renin to generate active renin, which in turn liberates angiotensin-I from angiotensinogen, placing KLKB1 upstream of the renin-angiotensin activation cascade, with kallikrein co-localizing with renin in juxtaglomerular cells (PMID:26969407). Loss of KLKB1 reduces arterial thrombosis through a defined signaling chain in which diminished bradykinin delivery elevates Mas receptor, prostacyclin, Sirt1, and KLF4 signaling and lowers vascular tissue factor (PMID:25339356). Beyond these roles, KLKB1 physically interacts with the transcription factor TFE3 to promote BRaf/MEK/ERK-driven ferroptosis in vascular dementia neurons (PMID:41242565).

1. 2014 High

   Established that KLKB1 loss is not merely a deficiency in clotting initiation but actively reprograms vascular signaling, answering how prekallikrein modulates thrombosis risk through downstream effector axes.

   Evidence Klkb1-/- mice with pharmacological rescue using Mas, COX-2, and Sirt1 inhibitors across multiple thrombosis models, with prostacyclin and aortic tissue factor readouts

   PMID:25339356

   Open questions at the time

   • Does not establish whether the Mas/prostacyclin/Sirt1/KLF4 axis operates identically in humans
   • The direct molecular link between reduced bradykinin and Mas receptor upregulation is inferred, not biochemically resolved
   • Does not address the catalytic mechanism of prekallikrein activation in this context
2. 2016 Medium

   Placed KLKB1 within the renin-angiotensin activation cascade by showing plasma kallikrein can directly convert pro-renin to active renin, answering whether kallikrein has a substrate beyond kininogen.

   Evidence In vitro enzymatic digestion of recombinant pro-renin by kallikrein with angiotensin-I generation readout, plus immunofluorescence co-localization in juxtaglomerular cells and kidney sections

   PMID:26969407

   Open questions at the time

   • Single-lab in vitro reconstitution; physiological contribution to renin activation in vivo not quantified
   • Co-localization does not demonstrate functional pro-renin processing in intact tissue
   • Cleavage site and kinetic parameters not defined
3. 2024 High

   Demonstrated a direct causal link between KLKB1 gene dosage and circulating kallikrein protein in humans, answering whether KLKB1 disruption is therapeutically sufficient to control kallikrein-driven disease.

   Evidence Phase 1 dose-escalation trial of in vivo CRISPR-Cas9 editing (NTLA-2002, lipid nanoparticle delivery) with plasma kallikrein quantification and angioedema attack-rate monitoring

   PMID:38294975

   Open questions at the time

   • Long-term durability of editing and off-target effects not addressed in this early-phase report
   • Does not characterize compensatory consequences of chronic kallikrein loss in humans
4. 2025 Medium

   Identified a non-canonical role for KLKB1 as a partner of transcription factor TFE3 driving neuronal ferroptosis, answering whether KLKB1 acts beyond plasma proteolysis.

   Evidence IP-MS and reciprocal Co-IP identifying TFE3 interaction, siRNA knockdown of KLKB1 and TFE3, and BRaf/MEK/ERK pathway readouts in a rat BCCAO vascular dementia model

   PMID:41242565

   Open questions at the time

   • Single-lab finding; the structural basis and cellular compartment of a protease-transcription factor interaction are undefined
   • Whether kallikrein catalytic activity is required for the TFE3/ferroptosis effect is unresolved
   • Mechanism by which KLKB1 knockdown lowers TFE3 expression is not established

• How a secreted plasma protease physically and functionally engages an intracellular transcription factor, and how its distinct kinin, renin, thrombosis, and ferroptosis roles are coordinated, remains unresolved.
• No structural model of the KLKB1-TFE3 complex
• No reconciliation of secreted versus intracellular function
• Relative physiological weighting of pro-renin versus kininogen substrates unquantified