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Target: SPATA2


Research on SPATA2

1. Target Summary:

SPATA2 (Spermatogenesis-associated protein 2) is a protein that plays a crucial role in various biological processes, including spermatogenesis, immune response regulation, and cancer progression. It is primarily known for its involvement in the recruitment and activation of the deubiquitinase CYLD within the TNF receptor signaling complex, influencing TNF-induced cell death and inflammatory responses. SPATA2 is significantly upregulated in various cancers, correlating with tumor progression and immune suppression.

2. Mechanism:

SPATA2 functions as a critical adaptor protein that links CYLD to the linear ubiquitin chain assembly complex (LUBAC). It interacts with CYLD through its non-canonical PUB domain, which binds to the catalytic USP domain of CYLD in a CYLD B-box-dependent manner (Elliott et al., 2016). This interaction activates CYLD, promoting the hydrolysis of ubiquitin chains and regulating immune signaling pathways, particularly those involving NF-kappaB (Elliott et al., 2021).
In the context of cancer, SPATA2 has been shown to influence the tumor microenvironment by modulating immune responses. For instance, SPATA2 is involved in the regulation of TNF-alpha signaling, which is crucial for maintaining the balance between pro-inflammatory and anti-inflammatory signals in tumors (Wieser et al., 2020). Additionally, SPATA2's role in regulating the NLRP3 inflammasome and its interaction with RNF213 highlight its importance in inflammatory cell death mechanisms in hypoxic tumors (Bhardwaj et al., 2025).

3. Approved Drugs:

Currently, there are no specific drugs approved that directly target SPATA2. However, therapies that modulate TNF-alpha signaling or target the pathways involving SPATA2 may have indirect effects on its function. Research is ongoing to explore potential therapeutic strategies that could target SPATA2 or its associated pathways in cancer treatment.

4. Hypotheses:

  1. Prognostic Marker: SPATA2 may serve as a prognostic marker in various cancers due to its correlation with tumor progression and immune suppression. High levels of SPATA2 expression are associated with poor clinical outcomes in endometrial cancer (Wieser et al., 2020).
  2. Therapeutic Target: Targeting SPATA2 could enhance the efficacy of immunotherapies in cancers resistant to conventional treatments, particularly by modulating immune responses in the tumor microenvironment (Bhardwaj et al., 2025).
  3. Role in Inflammation: SPATA2 may play a critical role in regulating inflammatory responses in various immune-related disorders, suggesting its potential as a therapeutic target in these conditions (Hrdinka & Gyrd-Hansen, 2017).

5. Validation:

The role of SPATA2 in cancer and immune responses has been validated through various studies. For instance, SPATA2's involvement in TNF-alpha signaling and its correlation with poor prognosis in endometrial cancer have been demonstrated through transcriptomic analyses (Wieser et al., 2020). Additionally, studies have shown that loss of SPATA2 leads to increased ubiquitination of LUBAC substrates and enhanced NOD2 signaling, confirming its regulatory role in immune signaling pathways (Elliott et al., 2016).

6. Clinical Trials:

As of now, there are no specific clinical trials targeting SPATA2 directly. However, ongoing research is exploring the implications of SPATA2 in cancer therapies, particularly in relation to TNF-alpha signaling and immune checkpoint inhibitors. Future trials may focus on the therapeutic potential of targeting SPATA2 in combination with existing cancer treatments.

7. Involved Pathways:

SPATA2 is primarily involved in the following pathways:
  • TNF Signaling Pathway: Regulates inflammatory responses and cell death mechanisms.
  • NF-kappaB Signaling Pathway: Modulates immune responses and cell survival.
  • Ubiquitin-Proteasome Pathway: Involves the regulation of protein degradation and signaling.

8. Associated Genes:

SPATA2 interacts with several key genes and proteins, including:
  • CYLD: A deubiquitinase that regulates NF-kappaB signaling.
  • LUBAC: A complex involved in linear ubiquitination and immune signaling.
  • RNF213: A protein implicated in inflammatory responses and cancer.

9. Target Expression:

SPATA2 is expressed in various tissues, with elevated levels observed in the testis and certain cancer types. Its expression is regulated by factors such as TNF-alpha and is associated with immune checkpoint genes and immune suppressive cells (Zhou et al., 2025).

10. Additional Context:

SPATA2's role extends beyond spermatogenesis, influencing immune responses and cancer progression. Its involvement in inflammatory processes and potential as a therapeutic target in cancer highlight its significance in both basic and clinical research.

11. References:

  • Elliott PR, Leske D, Hrdinka M. (2016). SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling. Molecular Cell. PMID: 27591049.
  • Elliott PR, Leske D, Wagstaff J. (2021). Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains. Cell Reports. PMID: 34610306.
  • Wieser V, Abdel Azim S, Sprung S. (2020). TNFalpha signalling predicts poor prognosis of patients with endometrial cancer. Carcinogenesis. PMID: 32301486.
  • Bhardwaj A, Panepinto MC, Ueberheide B. (2025). A mechanism for hypoxia-induced inflammatory cell death in cancer. Nature. PMID: 39506105.
  • Hrdinka M, Gyrd-Hansen M. (2017). The Met1-Linked Ubiquitin Machinery: Emerging Themes of (De)regulation. Molecular Cell. PMID: 29053955.
  • Zhou Y, Geng S, Tang RC. (2025). Clinical and functional significance of SPATA2 in cancer particularly in LIHC. Scientific Reports. PMID: 40069269.