ATG proteins in CP/CPPS–evidence and pathogenic implications.
| Protein | Proposed pathogenic consequence in CP/CPPS | Primary function in autophagy | Evidence of dysregulation in CP/CPPS |
|---|---|---|---|
| ULK1 | Stress signaling via mTOR/AMPK may be dysregulated, impairing autophagy initiation in prostate cells, contributing to DAMP accumulation. | Serine/threonine kinase and mammalian ATG1 homolog; forms the ULK1–ATG13–FIP200–ATG101 complex to initiate autophagosome formation. Its activity is directly inhibited by mTORC1 phosphorylation under nutrient-rich conditions and activated by AMPK phosphorylation during cellular stress [93]. | No direct CP/CPPS data reported. Role inferred from its position as a master stress sensor in other chronic inflammatory models. |
| Beclin 1 (BECN1) | If its expression or activity were reduced in CP/CPPS, it could impair phagophore formation, compromising the clearance of damaged components and potentially promoting inflammasome-driven inflammation. | Core subunit of the class III PI3K (PI3KC3) complex; essential for generating PI(3)P to initiate phagophore nucleation and autophagosome formation [94, 95]. | No direct CP/CPPS data reported. Its role is inferred from its established function as a key autophagy regulator and its dysregulation in other inflammatory conditions. |
| LC3 (MAP1LC3B) | The presence of LC3-II in prostate-derived exosomes suggests that autophagic activity may contribute to exosome biogenesis or cargo selection. It represents a potential candidate biomarker for prostate cellular stress. | Ubiquitin-like protein processed to the lipidated form LC3-II (LC3-PE), which stably associates with autophagosomal membranes and serves as the canonical, gold-standard marker for monitoring autophagic flux [96, 97]. | No direct CP/CPPS data reported. The presence of ATG proteins in prostate-derived exosomes from patients remains an unexplored area. |
| ATG5 | Functional deficiency would halt autophagy, leading to the accumulation of damaged organelles and proteins, triggering oxidative stress and cytokine release. | Forms a conjugate with ATG12; essential for phagophore elongation. | No direct CP/CPPS data reported. Comprehensive reviews of CP/CPPS pathogenesis and biomarker studies (e.g., focusing on S100A12, IL-8, oxidative stress mediators) do not include analysis of ATG5 or core autophagy genes, indicating this remains an uninvestigated area [98, 99]. |
| ATG7 | As a master regulator, its dysfunction would broadly disable autophagy, creating a pro-inflammatory cellular state. | E1-like activating enzyme; essential for ATG12-ATG5 conjugation and LC3 lipidation. | No direct CP/CPPS data reported [99, 100]. |
| p62/SQSTM1 | p62 accumulation acts as a persistent signaling hub, activating pro-inflammatory pathways (e.g., NF-κB, NRF2) and promoting chronic tissue inflammation. | Autophagy receptor that links ubiquitinated cargo to LC3; degraded via autophagy. | Significant accumulation in stromal and epithelial cells of CP/CPPS patient prostate biopsies [101]. |
AMPK: AMP-activated protein kinase; ATG: autophagy-related; CP/CPPS: chronic prostatitis/chronic pelvic pain syndrome; DAMP: damage-associated molecular pattern; LC3: microtubule-associated protein 1 light chain 3; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor kappa B; NRF2: nuclear factor erythroid 2-related factor 2; PE: phosphatidylethanolamine; PI3K: phosphatidylinositol 3-kinase; ULK1: Unc-51-like kinase 1.
DKN: Conceptualization, Investigation, Writing—original draft, Writing—review & editing, Visualization. FG: Formal analysis, Visualization. EDKF: Writing—review & editing. AA: Writing—review & editing, Data curation. BRO: Data curation, Visualization. FA: Data curation, Project administration. XZ: Supervision, Project administration, Writing—review & editing, Resources. All authors read and approved the submitted version.
The authors declare that they have no conflicts of interest.
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