Affinage

TPP2

Tripeptidyl-peptidase 2 · UniProt P29144

Length
1249 aa
Mass
138.3 kDa
Annotated
2026-06-10
17 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TPP2 (TPPII) is a giant cytosolic serine exopeptidase that operates downstream of the 26S proteasome, assembling into large spindle-shaped complexes that exist in two distinct oligomeric states (36-mers and 32-mers) and spatially associate with proteasomes in situ to process peptides released from proteasomal degradation (PMID:28396430). In MHC class I antigen processing it plays a predominantly destructive role: by cleaving proteasomally generated peptide fragments through combined endo- and exoproteolytic activity, it limits the supply of antigenic epitopes, such that TPPII loss delays fragment degradation and elevates surface MHC-I peptide complexes, SIINFEKL presentation, and cross-presentation (PMID:15224091, PMID:18056356). Beyond peptide trimming, TPPII regulates cell survival and proliferation in a cell-type-specific manner: its loss in mice activates p53-dependent proliferative apoptosis in T cells and premature senescence in fibroblasts and CD8+ T cells with dysregulated NF-κB, producing immunosenescence-like phenotypes (PMID:18362329), whereas its overexpression shortens mitosis, upregulates IAPs, and allows cells to evade spindle-checkpoint-mediated apoptosis and become polyploid (PMID:16762321); this survival requirement is not universal, as TPPII deletion does not impair viability or the p53 DNA-damage response in Myc/Ras-transformed fibroblasts (PMID:19539606). TPPII forms physical complexes with the cell-cycle regulator CDK2 and the tumor suppressor MYBBP1A, an interaction blocked by the TPPII inhibitor butabindide (PMID:25303791). Upon proteasome inhibition, TPPII relocalizes from a diffuse cytoplasmic distribution to perinuclear aggresomes, forming a mantle around the proteasome/polyubiquitin core (PMID:30226264).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2004 Medium

    Established where TPPII acts in the antigen-processing pathway, resolving whether it generates or destroys MHC class I epitopes by placing it downstream of the proteasome with dual proteolytic activities.

    Evidence Synthesis of in vitro and functional antigen-processing assays in a review

    PMID:15224091

    Open questions at the time
    • Relative contribution of endo- versus exoproteolytic activity not quantified
    • Does not establish which specific epitopes are net-generated versus net-destroyed in vivo
  2. 2006 Medium

    Linked TPPII to mitotic progression and apoptosis evasion, showing it can shorten the cell cycle and confer resistance to spindle-checkpoint death.

    Evidence Overexpression and shRNA knockdown in HEK293 cells with cell-cycle, polyploidy, and apoptosis readouts

    PMID:16762321

    Open questions at the time
    • Single cell line and single lab
    • Mechanism linking peptidase activity to IAP upregulation not defined
    • Direct substrate driving the mitotic phenotype unidentified
  3. 2007 High

    Genetically confirmed TPPII's predominantly destructive role in antigen processing by showing its loss delays peptide fragment degradation and raises MHC-I presentation.

    Evidence TPPII-knockout mouse with cytosolic peptide degradation assays, flow cytometry, and CTL presentation assays

    PMID:18056356

    Open questions at the time
    • Does not exclude epitope-generating roles for specific antigens
    • Redundancy with other cytosolic peptidases not addressed
  4. 2008 High

    Revealed a cell-survival function distinct from peptidase activity, showing TPPII loss triggers cell-type-specific p53-dependent apoptosis and senescence and drives immunosenescence.

    Evidence TPPII knockout mouse with apoptosis/senescence markers, p53 and NF-κB western blotting, and immunophenotyping

    PMID:18362329

    Open questions at the time
    • Molecular link between TPPII loss and p53 stabilization not defined
    • Why fibroblasts senesce while T cells undergo apoptosis is unexplained
  5. 2009 Medium

    Bounded the survival requirement by showing TPPII is dispensable for viability, proliferation, and the p53 DNA-damage response in transformed fibroblasts.

    Evidence Conditional floxed allele deletion in Myc/Ras-transformed fibroblasts with clonogenic, cell-cycle, and p53/p21 readouts

    PMID:19539606

    Open questions at the time
    • Negative result restricted to transformed fibroblasts
    • Does not reconcile with apoptosis/senescence seen in primary cells
  6. 2014 Medium

    Identified direct protein partners of TPPII, connecting it physically to a cell-cycle kinase and a tumor suppressor and showing the interaction is inhibitor-sensitive.

    Evidence Co-immunoprecipitation, in situ proximity ligation assay, butabindide inhibition, and qRT-PCR in HEK293 cells

    PMID:25303791

    Open questions at the time
    • Single lab without reciprocal validation of functional consequence
    • Whether MYBBP1A/CDK2 are substrates or stable binding partners unresolved
  7. 2015 Low

    Extended the TPPII interactome to p53 and SIRT7 across cytoplasmic and nuclear compartments, hinting at a nuclear regulatory role.

    Evidence Co-immunoprecipitation from cell lysates and tissue fractions, PLA, and immunofluorescence

    PMID:26169984

    Open questions at the time
    • No functional consequence or reciprocal validation demonstrated
    • Nuclear localization of a cytosolic peptidase not mechanistically explained
  8. 2017 High

    Resolved the in situ architecture and spatial behaviour of TPPII, confirming two oligomeric assembly states and physical proximity to proteasomes consistent with post-proteasomal processing.

    Evidence Cryo-electron tomography of rat hippocampal neurons with template matching and distance analysis

    PMID:28396430

    Open questions at the time
    • Functional significance of the 36-mer versus 32-mer states not defined
    • Does not establish whether proximity reflects direct hand-off of substrates
  9. 2018 Medium

    Showed TPPII localization is dynamic and proteasome-state-dependent, redistributing into aggresomes when proteasomal function is impaired.

    Evidence Confocal microscopy with fluorescent proteasome inhibitor and co-immunofluorescence in C26 cells

    PMID:30226264

    Open questions at the time
    • Functional role of aggresomal TPPII unknown
    • Recruitment mechanism to aggresomes not identified
  10. 2022 Low

    Implicated TPPII in autophagy-dependent CTL activation against HBV, suggesting a role in antiviral immunity via the PI3K/Akt/mTOR axis.

    Evidence Adenoviral TPPII vector in HBV transgenic and ATG5-knockout mice with TEM, LC3/BECN1 westerns, and ELISA

    PMID:34902200

    Open questions at the time
    • Pathway placement inferred, not demonstrated by mutagenesis or reconstitution
    • Single lab in vivo model
    • Direct molecular link between TPPII peptidase activity and autophagy induction missing

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TPPII's enzymatic peptidase function mechanistically connects to its survival, mitotic, and p53/CDK2/MYBBP1A regulatory roles remains unresolved.
  • No demonstrated catalytic substrate explains the cell-cycle or apoptosis phenotypes
  • Whether partner interactions require TPPII catalytic activity is untested
  • Structural basis for switching between assembly states and its functional output is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3
Partners
CDK2MYBBP1ASIRT7TP53

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 Cryo-electron tomography of rat hippocampal neurons revealed that TPPII exists in two assembly states (36-mers and 32-mers) in situ, and distance analysis confirmed that TPPII complexes spatially associate with 26S proteasomes in the cellular environment, consistent with its role in post-proteasomal degradation. Cryo-electron tomography with Volta phase plate, template matching, and distance analysis in situ Proceedings of the National Academy of Sciences of the United States of America High 28396430
2004 TPPII acts downstream of the proteasome in MHC class I antigen processing, using both endoproteolytic and exoproteolytic activities to process proteasomal degradation products; its activity can generate or destroy antigenic peptide epitopes. Biochemical review integrating in vitro assays and functional antigen-processing studies (review/synthesis of experimental literature) Nature immunology Medium 15224091
2007 In TPPII-knockout mice, degradation of proteasomally generated OVA peptide fragments was delayed in cytosolic extracts, demonstrating that TPPII plays a predominantly destructive role in MHC class I antigen processing by cleaving these fragments. Surface MHC-I peptide complexes and presentation of the OVA SIINFEKL epitope were increased in TPPII-deficient cells. Cross-presentation of phagocytosed OVA by dendritic cells was also increased. Genetic knockout mouse model; peptide degradation assays in cytosolic extracts; flow cytometry for MHC-I surface levels; CTL-based antigen presentation assays Journal of immunology (Baltimore, Md. : 1950) High 18056356
2008 TPPII deficiency in mice activates cell type-specific death programs: proliferative apoptosis in T cell subsets and premature cellular senescence in fibroblasts and CD8+ T cells, coinciding with upregulation of p53 and dysregulation of NF-κB. TPPII-deficient mice show accelerated thymic involution, lymphopenia, and immunosenescence-like phenotypes. TPPII knockout mouse model; apoptosis assays; senescence markers; p53 and NF-κB western blotting; immunophenotyping Proceedings of the National Academy of Sciences of the United States of America High 18362329
2006 TPPII overexpression in HEK293 cells reduces the length of mitosis and the cell cycle, correlates with upregulation of IAPs, and confers resistance to mitochondria-dependent apoptosis induced by p53 stabilization. TPPII knockdown by shRNA slows cell growth and causes accumulation of cells failing to complete mitosis. TPPII overexpressing cells evade mitotic arrest from spindle poisons and show polyploidy despite intact spindle checkpoint components. Overexpression and shRNA knockdown in HEK293 cells; flow cytometry cell cycle analysis; polyploidy assessment; apoptosis assays; western blotting for IAPs and spindle checkpoint proteins Biochemical and biophysical research communications Medium 16762321
2009 Genetic deletion of TPPII in Myc- and Ras-transformed fibroblasts had no effect on basal cell survival, proliferation, or radiation-induced p53 activation, p21 induction, cell cycle arrest, apoptosis, or clonogenic cell death, indicating that TPPII is NOT generally required for viability, proliferation, or p53-mediated DNA damage response of transformed cells. Conditional (floxed) TPPII allele deletion via Cre recombinase in transformed fibroblast cell lines; clonogenic survival assays; western blotting for p53, p21; cell cycle analysis Biochemical and biophysical research communications Medium 19539606
2014 TPPII physically interacts with tumor suppressor MYBBP1A and cell cycle regulator CDK2, as detected by co-immunoprecipitation and in situ proximity ligation assay in HEK293 cells. The TPPII inhibitor butabindide suppressed the cytoplasmic interaction between TPPII and MYBBP1A. Overexpression of TPPII decreased MYBBP1A mRNA during anoikis conditions. Co-immunoprecipitation; in situ proximity ligation assay (PLA); butabindide pharmacological inhibition; quantitative RT-PCR for mRNA levels Archives of biochemistry and biophysics Medium 25303791
2015 TPPII physically interacts with p53 and with SIRT7 in both cytoplasmic and nuclear compartments, as detected by co-immunoprecipitation from HeLa lysates and mouse liver cytoplasm and confirmed by in situ proximity ligation assay in HEK293 cells. These interactions were detected in both control and TPPII-overexpressing cells. Co-immunoprecipitation from cell lysates and tissue fractions; in situ proximity ligation assay (PLA); immunofluorescence Molecular and cellular biochemistry Low 26169984
2018 In C26 murine colon adenocarcinoma cells, TPPII is diffusely dispersed in the cytoplasm under normal conditions. Upon proteasome inhibition, TPPII is dynamically recruited to the perinuclear region and into aggresome structures, where it ultimately forms a spherical mantle surrounding the proteasome/polyubiquitinated protein core, demonstrating spatial co-localization with proteasomes especially when proteasomal function is impaired. Laser scanning confocal microscopy; fluorescent proteasome inhibitor (BSc2118) for in vivo proteasome staining; co-immunofluorescence for TPPII and polyubiquitinated proteins Histology and histopathology Medium 30226264
2022 An adenovirus vector encoding TPPII (Adv-HBcAg-TPPII) activated autophagy in CD8+ T cells in HBV transgenic mice, induced CTL responses, and inhibited HBV DNA replication and HBsAg expression. The mechanism appeared to involve the PI3K/Akt/mTOR signalling pathway. In ATG5-knockout HBV transgenic mice, this TPPII-driven effect was abrogated. In vivo immunization of HBV transgenic and ATG5 KO mice with adenoviral vector; transmission electron microscopy; immunofluorescence; western blot for LC3 and BECN1; ELISA for HBV markers; immunohistochemistry Journal of viral hepatitis Low 34902200

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Generation of major histocompatibility complex class I antigens: functional interplay between proteasomes and TPPII. Nature immunology 179 15224091
2008 Activation of cellular death programs associated with immunosenescence-like phenotype in TPPII knockout mice. Proceedings of the National Academy of Sciences of the United States of America 33 18362329
2007 Analysis of direct and cross-presentation of antigens in TPPII knockout mice. Journal of immunology (Baltimore, Md. : 1950) 33 18056356
2017 In situ structural studies of tripeptidyl peptidase II (TPPII) reveal spatial association with proteasomes. Proceedings of the National Academy of Sciences of the United States of America 24 28396430
2015 Novel protein-protein interactions of TPPII, p53, and SIRT7. Molecular and cellular biochemistry 22 26169984
2006 TPPII promotes genetic instability by allowing the escape from apoptosis of cells with activated mitotic checkpoints. Biochemical and biophysical research communications 22 16762321
1993 Assignment of the linkage group EAM-TYRP2-TPP2 to chromosome 11 in pigs by in situ hybridization mapping of the TPP2 gene. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 13 7908839
2018 TPP2 mutation associated with sterile brain inflammation mimicking MS. Neurology. Genetics 7 30533531
2014 TPPII, MYBBP1A and CDK2 form a protein-protein interaction network. Archives of biochemistry and biophysics 7 25303791
2009 Viability and DNA damage responses of TPPII-deficient Myc- and Ras-transformed fibroblasts. Biochemical and biophysical research communications 7 19539606
2021 Immune deficiency, autoimmune disease and intellectual disability: A pleiotropic disorder caused by biallelic variants in the TPP2 gene. Clinical genetics 6 33586135
1993 Localization of the human tripeptidyl peptidase II gene (TPP2) to 13q32-q33 by nonradioactive in situ hybridization and somatic cell hybrids. Genomics 5 8406500
2022 Adenovirus vector encoding TPPII ignites HBV-specific CTL response by activating autophagy in CD8+ T cell. Journal of viral hepatitis 3 34902200
2020 Linking TPPII to the protein interaction and signalling networks. Computational biology and chemistry 2 32702546
2018 Semispecific TPPII inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk) displays cytotoxic activity by induction of apoptosis, autophagy and protein aggregation in U937 cells. Folia histochemica et cytobiologica 2 30294774
2006 Overlapping regional distribution of CCK and TPPII mRNAs in Cynomolgus monkey brain and correlated levels in human cerebral cortex (BA 10). Brain research 2 16822484
2018 Changes in spatio-temporal localization of tripeptidyl peptidase II (TPPII) in murine colon adenocarcinoma cells during aggresome formation: a microscopy study based on a novel fluorescent proteasome inhibitor. Histology and histopathology 1 30226264

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