CTSZ

CTSZ encodes cathepsin Z, a cysteine protease that functions across multiple oncogenic and immune signaling contexts to drive cell migration, survival, and the recruitment of immunosuppressive myeloid cells (PMID:30018008, PMID:40976418). In cancer cells, CTSZ binds integrin β3 to activate downstream FAK/Src/Paxillin signaling, promoting migration and invasion (PMID:30018008), and it forms a complex with TYROBP that activates a pAKT-CD44 axis and accelerates glycolysis to support metastasis (PMID:40976418). CTSZ remodels the tumor microenvironment by inducing proteasomal degradation of TRA2A, relieving suppression of IL32 alternative splicing so that secreted IL-32 engages macrophage integrin ITGA5 and recruits M2 tumor-associated macrophages (PMID:40764928). It also sustains tumor cell survival by activating NF-κB signaling to confer anoikis resistance, with knockdown impairing nuclear translocation of NF-κB p65 (PMID:42231963). CTSZ translation is held in check by PDCD4, which binds an IRES element in the CTSZ 5' UTR, linking CTSZ to apoptotic regulation downstream of PDCD4 (PMID:39190024). Beyond cancer, CTSZ restrains macrophage CXCL1 production to limit Mycobacterium tuberculosis burden and disease severity, localizing to granuloma-associated macrophages at the host-pathogen interface [PMID:bio_10.1101_2025.04.01.644622].

1. 2000 Low

   Before functional characterization, the basic gene architecture and regulatory status of CTSZ were undefined; this work established CTSZ as a six-exon cysteine protease gene that is biallelically (non-imprinted) expressed.

   Evidence Genomic structure determination and SNP-based allelic expression analysis in human fetal tissues

   PMID:11030415

   Open questions at the time

   • No functional or enzymatic mechanism assayed
   • Protease substrates and catalytic role not addressed
2. 2018 Medium

   It was unknown how CTSZ promotes tumor cell motility; identifying the integrin β3 interaction connected CTSZ to FAK/Src/Paxillin signaling as the route to migration and invasion.

   Evidence Co-immunoprecipitation, siRNA knockdown, in vitro migration/invasion assays, and in vivo metastasis model in NSCLC

   PMID:30018008

   Open questions at the time

   • Whether proteolytic activity is required for integrin β3 engagement not resolved
   • Single lab
3. 2024 Medium

   The upstream control of CTSZ expression was unclear; PDCD4 was shown to bind an IRES in the CTSZ 5' UTR and suppress its translation, placing CTSZ in a translational-regulation/apoptosis pathway in multiple myeloma.

   Evidence RIP-seq, RNA pull-down, dual luciferase IRES reporter, knockdown, and apoptosis rescue with CTSZ inhibitors

   PMID:39190024

   Open questions at the time

   • Mechanism by which CTSZ inhibits apoptosis downstream not detailed
   • Single lab
4. 2025 Medium

   How CTSZ reshapes the immune microenvironment was unknown; it was shown to drive proteasomal degradation of the splicing factor TRA2A, deregulating IL32 splicing so that IL-32 recruits M2 macrophages via ITGA5.

   Evidence Proteasomal degradation and splicing assays, IL-32/RGD binding experiments, CTSZ overexpression in metastatic mouse models, ITGA5 inhibitor treatment

   PMID:40764928

   Open questions at the time

   • Whether CTSZ protease activity directs TRA2A degradation not established
   • Single lab in prostate cancer only
5. 2025 Medium

   An additional CTSZ signaling complex was defined: TYROBP partnering with CTSZ enhances CXCL8-mediated TAM recruitment and activates pAKT-CD44 signaling with increased glycolysis to promote pancreatic cancer metastasis.

   Evidence Co-immunoprecipitation, gain/loss-of-function studies, in vivo metastasis models, pharmacological inhibition with baicalein

   PMID:40976418

   Open questions at the time

   • Structural basis of the CTSZ-TYROBP complex unknown
   • Relationship to the integrin β3 axis not integrated
6. 2025 Medium

   The role of CTSZ in infection was unresolved; loss of Ctsz in mice and macrophages caused CXCL1 overproduction and increased M. tuberculosis burden, defining a protective CTSZ-CXCL1 axis with human CTSZ at the granuloma host-pathogen interface.

   Evidence Ctsz knockout and Collaborative Cross mouse panels, bacterial burden and cytokine measurement, survival analysis, IHC in human granulomas, human genetic association (preprint)

   PMID:bio_10.1101_2025.04.01.644622

   Open questions at the time

   • Molecular mechanism by which CTSZ restrains CXCL1 not defined
   • Preprint, not peer-reviewed
7. 2026 Medium

   It was unclear how CTSZ supports tumor cell survival under detachment; CTSZ was shown to confer anoikis resistance in glioblastoma by promoting NF-κB p65 nuclear translocation.

   Evidence siRNA knockdown, anoikis sensitivity assays, NF-κB p65 nuclear translocation assay in GBM cells

   PMID:42231963

   Open questions at the time

   • Link between CTSZ and NF-κB activation mechanistically undefined
   • Single lab

• Whether the catalytic protease activity of cathepsin Z is required for its diverse signaling functions, and how its multiple interaction partners are integrated, remains unresolved.
• No structural model of CTSZ complexes
• Substrate repertoire underlying signaling not defined
• Unifying mechanism across cancer and infection contexts absent