Affinage

HPN

Serine protease hepsin · UniProt P05981

Length
417 aa
Mass
45.0 kDa
Annotated
2026-06-10
39 papers in source corpus 3 papers cited in narrative 3 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HPN encodes hepsin/TMPRSS1, a serine protease required for cochlear development and normal auditory function, as established by knockout mice that display profound hearing loss with elevated thresholds, abnormal tectorial membrane development, reduced auditory-nerve myelin proteins (MBP, MPZ), diminished hair-cell BK channel expression, and reduced free thyroxine (PMID:17620368). Its proteolytic activity is essential for this role: transgenic re-expression of wild-type hepsin, but not a protease-dead active-site (S→A) mutant, partially restores hearing thresholds and tectorial membrane compaction and attachment to the spiral limbus in knockout mice (PMID:39437584). Mechanistically, hepsin co-localizes with the tectorial membrane proteins α-tectorin (TECTA) and β-tectorin (TECTB) in developing cochlear epithelium, and their reduced levels in knockout tectorial membrane are partially rescued by hepsin re-expression, consistent with hepsin proteolytically maturing TECTA and TECTB for incorporation into the tectorial membrane (PMID:39437584). A separate mouse genetic study additionally links reduced Hpn expression to lowered serum HDL and non-HDL cholesterol and triglycerides, placing the gene in hepatic lipoprotein metabolism (PMID:22912808).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2007 High

    Established that hepsin/TMPRSS1 is required in vivo for auditory development, answering whether the protease has a non-redundant physiological function.

    Evidence Knockout mouse with auditory brainstem response, cochlear histology, myelin and BK-channel immunostaining, and thyroid hormone assay

    PMID:17620368

    Open questions at the time
    • Did not identify direct proteolytic substrates
    • Could not distinguish whether phenotypes depend on catalytic activity versus a structural role
    • Mechanism linking the protease to thyroxine and myelin changes unresolved
  2. 2012 Medium

    Linked HPN loss-of-function to hepatic lipoprotein metabolism, extending its physiological reach beyond the cochlea.

    Evidence ENU mutagenesis, linkage mapping, and serum lipid profiling in mouse with a splice-site Hpn mutation

    PMID:22912808

    Open questions at the time
    • No direct molecular mechanism for the lipid phenotype identified
    • Pathway placement rests on a single genetic approach
    • No protease substrate in lipid metabolism defined
  3. 2024 High

    Demonstrated that hepsin's catalytic activity drives tectorial membrane morphogenesis and identified candidate substrates, converting a phenotypic requirement into a proteolytic mechanism.

    Evidence In vivo transgenic rescue with wild-type versus protease-dead hepsin, auditory brainstem response, cochlear histology, and TECTA/TECTB immunostaining

    PMID:39437584

    Open questions at the time
    • Direct cleavage of TECTA/TECTB not demonstrated biochemically
    • Cleavage sites and processing products unmapped
    • Rescue was only partial, leaving room for additional substrates or functions

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether hepsin directly cleaves TECTA/TECTB and how its proteolytic activity connects to myelin, BK-channel, thyroxine, and lipoprotein phenotypes remains unresolved.
  • No in vitro reconstitution of TECTA/TECTB cleavage
  • No defined substrate for the lipid metabolism role
  • Mechanistic basis of pleiotropy (hearing, thyroid, myelin) unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 2 GO:0140096 catalytic activity, acting on a protein 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1430728 Metabolism 1
Partners
TECTATECTB

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Hepsin/TMPRSS1 knockout mice exhibit profound hearing loss with elevated hearing thresholds, abnormal tectorial membrane development, reduced myelin protein expression (MBP and MPZ) in the auditory nerve, decreased large conductance voltage- and Ca2+-activated K+ channel in sensory hair cells, and significantly reduced free thyroxine levels, establishing TMPRSS1 as required for normal auditory function and cochlear development. Knockout mouse model; auditory brainstem response threshold measurement; cochlear histology; immunostaining for myelin proteins and BK channel; thyroid hormone assay The American journal of pathology High 17620368
2024 The serine protease activity of hepsin/TMPRSS1 is critical for tectorial membrane morphogenesis and hearing function; transgenic rescue with wild-type human hepsin (but not a protease-dead S→A active-site mutant) partially restored hearing thresholds and tectorial membrane compaction and attachment to the spiral limbus in knockout mice. Hepsin co-localizes with α-tectorin (TECTA) and β-tectorin (TECTB) in developing cochlear epithelium, and their levels are decreased in the knockout TM and partially restored by hepsin re-expression, suggesting hepsin proteolytically processes/maturates TECTA and TECTB for TM incorporation. Transgenic rescue with wild-type vs. protease-dead hepsin in knockout background; auditory brainstem response; cochlear histology; immunostaining for TECTA/TECTB Hearing research High 39437584
2012 A splice-site mutation in mouse Hpn (hepsin/TMPRSS1) causing ~7-fold downregulation of Hpn mRNA leads to reduced serum HDL cholesterol, non-HDL cholesterol, and triglyceride levels, placing HPN in the pathway of hepatic lipoprotein metabolism as identified by ENU mutagenesis and linkage mapping. ENU mutagenesis; linkage analysis; RNA sequencing; Northern blot; microarray PloS one Medium 22912808

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Protein Hpn: cloning and characterization of a histidine-rich metal-binding polypeptide in Helicobacter pylori and Helicobacter mustelae. Infection and immunity 95 7790085
2006 Expression and characterization of a histidine-rich protein, Hpn: potential for Ni2+ storage in Helicobacter pylori. The Biochemical journal 78 16164421
2006 Thermodynamic and kinetic aspects of metal binding to the histidine-rich protein, Hpn. Journal of the American Chemical Society 59 16939237
2007 Roles of His-rich hpn and hpn-like proteins in Helicobacter pylori nickel physiology. Journal of bacteriology 56 17384182
2007 Mice deficient for the type II transmembrane serine protease, TMPRSS1/hepsin, exhibit profound hearing loss. The American journal of pathology 56 17620368
1999 Role of Hpn and NixA of Helicobacter pylori in susceptibility and resistance to bismuth and other metal ions. Helicobacter 47 10469190
2008 Binding of Ni2+ to a histidine- and glutamine-rich protein, Hpn-like. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 45 18563455
1999 The human prolactin receptor gene structure and alternative promoter utilization: the generic promoter hPIII and a novel human promoter hP(N). The Journal of clinical endocrinology and metabolism 45 10084611
2012 Architecture of the catalytic HPN motif is conserved in all E2 conjugating enzymes. The Biochemical journal 37 22563859
2011 The -Cys-Cys- motif in Helicobacter pylori's Hpn and HspA proteins is an essential anchoring site for metal ions. Dalton transactions (Cambridge, England : 2003) 36 21503353
2013 HPN, a synthetic analogue of bromophenol from red alga Rhodomela confervoides: synthesis and anti-diabetic effects in C57BL/KsJ-db/db mice. Marine drugs 31 23364683
2017 Ubiquitin specific peptidase 5 mediates Histidine-rich protein Hpn induced cell apoptosis in hepatocellular carcinoma through P14-P53 signaling. Proteomics 30 28523650
2008 What information should lead to a suspicion of catheter sepsis in HPN? Clinical nutrition (Edinburgh, Scotland) 30 18662842
2011 Metal-binding properties of an Hpn-like histidine-rich protein. Chemistry (Weinheim an der Bergstrasse, Germany) 26 21520306
2020 LncRNA TRPC7-AS1 regulates nucleus pulposus cellular senescence and ECM synthesis via competing with HPN for miR-4769-5p binding. Mechanisms of ageing and development 25 32585234
2012 The coordination of NiII and Cu(II) ions to the polyhistidyl motif of Hpn protein: is it as strong as we think? Chemistry (Weinheim an der Bergstrasse, Germany) 25 22829429
2017 Selectivity, cell permeability and oral availability studies of novel bromophenol derivative HPN as protein tyrosine phosphatase 1B inhibitor. British journal of pharmacology 24 29059712
2010 Cu2+ and Ni2+ interactions with N-terminal fragments of Hpn and Hpn-like proteins from Helicobacter pylori: unusual impact of poly-Gln sequence on the complex stability. Journal of inorganic biochemistry 24 21194620
2012 Pla2g12b and Hpn are genes identified by mouse ENU mutagenesis that affect HDL cholesterol. PloS one 21 22912808
2011 Histidine-rich protein Hpn from Helicobacter pylori forms amyloid-like fibrils in vitro and inhibits the proliferation of gastric epithelial AGS cells. Biochimica et biophysica acta 17 21539864
2011 The in vivo functions of a histidine-rich protein Hpn in Helicobacter pylori: linking gastric and Alzheimer's diseases together? Medical hypotheses 17 21852052
2020 L1CAM, CA9, KLK6, HPN, and ALDH1A1 as Potential Serum Markers in Primary and Metastatic Colorectal Cancer Screening. Diagnostics (Basel, Switzerland) 14 32630086
2017 HPN-07, a free radical spin trapping agent, protects against functional, cellular and electrophysiological changes in the cochlea induced by acute acoustic trauma. PloS one 14 28832600
2020 The N-terminal domain of Helicobacter pylori's Hpn protein: The role of multiple histidine residues. Journal of inorganic biochemistry 13 33197826
2013 Identifying patient-centered quality indicators for the care of adult home parenteral nutrition (HPN) patients. JPEN. Journal of parenteral and enteral nutrition 13 23894172
2017 A novel mechanism of "metal gel-shift" by histidine-rich Ni2+-binding Hpn protein from Helicobacter pylori strain SS1. PloS one 11 28207866
2022 A novel nitronyl nitroxide radical HPN-C6 attenuates brain damage in an acute hypobaric hypoxia mouse model through inhibition of the oxidative stress. Neuroscience letters 8 35469823
2021 A Comparative Study on Nickel Binding to Hpn-like Polypeptides from Two Helicobacter pylori Strains. International journal of molecular sciences 8 34948007
2014 Selective interaction of Hpn-like protein with nickel, zinc and bismuth in vitro and in cells by FRET. Journal of inorganic biochemistry 5 25299958
2023 A one size vial does not fit all: An evaluation of the micronutrient status of adult patients receiving home parenteral nutrition (HPN). Clinical nutrition ESPEN 4 37739722
2021 Personalized exercise intervention in HPN patients - A feasibility study. Clinical nutrition ESPEN 4 34620349
2016 Strategies for early metabolic disturbances in patients with an end jejunostomy or end ileostomy. Experience from a specialized Home Parenteral Nutrition (HPN) center. Przeglad gastroenterologiczny 4 28702099
2024 GABPA-Mediated Expression of HPN-AS1 Facilitates Cell Apoptosis and Inhibits Cell Proliferation in Hepatocellular Carcinoma by Promoting eIF4A3 Degradation. The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology 3 39114737
2024 Ultrasound-guided renal artery balloon catheter occluded hybrid partial nephrectomy (UBo-HPN) with branch renal artery occlusion: a single arm trial. World journal of urology 3 39382799
2023 KIAA1429 facilitates progression of hepatocellular carcinoma by modulating m6A levels in HPN. Heliyon 3 38058614
2014 The interaction of a histidine-rich protein hpn with the membrane mimics: implications for pathologic roles of Hpn in Helicobacter pylori. Helicobacter 3 24494595
2013 Inhibition of Helicobacter pylori urease activity in vivo by the synthetic nickel binding protein Hpn. European journal of microbiology & immunology 2 24265922
2024 Critical role of hepsin/TMPRSS1 in hearing and tectorial membrane morphogenesis: Insights from transgenic mouse models. Hearing research 1 39437584
2023 Safety evaluation of the food enzyme bacillolysin from the non-genetically modified Bacillus amyloliquefaciens strain HPN 131. EFSA journal. European Food Safety Authority 1 38027440

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