PDCD5 (Programmed cell death protein 5, also known as TFAR19) is a pro-apoptotic regulatory adaptor protein that functions primarily as a positive regulator of the p53/TP53 tumor suppressor pathway. Under normal conditions, PDCD5 helps maintain basal levels of p53 and Tip60 (a histone acetyltransferase). Upon DNA damage or genotoxic stress, PDCD5 is phosphorylated at Ser-119 by CK2, which stabilizes the protein and promotes its translocation from cytosol to nucleus. In the nucleus, PDCD5 performs two key functions: (1) it binds to and activates Tip60, enhancing its HAT activity and Tip60-dependent K120 acetylation of p53; (2) it directly binds p53 and antagonizes MDM2-mediated p53 ubiquitination and degradation, thereby stabilizing p53 and promoting p53-dependent transcription of pro-apoptotic genes (BAX, PUMA). PDCD5 is also regulated by OTUD5 (deubiquitinase that stabilizes it) and JMJD4/PPEF-1 (which promote its degradation). Beyond apoptosis, PDCD5 interacts with FOXP3 to enhance Treg function and suppress autoimmunity. It also inhibits beta-tubulin folding by binding to the CCT chaperonin complex, which may contribute to its anti-proliferative effects.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: PDCD5 nuclear localization is well-documented and represents a key functional location, particularly during genotoxic stress responses. Multiple primary studies demonstrate nuclear localization by immunofluorescence and fractionation [PMID:19308289, PMID:22914926, PMID:28051100, PMID:24012345]. The IBA annotation is consistent with phylogenetic conservation and experimental data. Reason: Nuclear localization is essential for PDCD5 function in p53 activation and DNA damage response. CK2-mediated phosphorylation at Ser-119 promotes nuclear translocation during genotoxic stress [PMID:28051100]. Supporting Evidence: PMID:28051100 PDCD5 phosphorylation at Ser-119 is rapidly induced by the genotoxic stress response, which stabilizes the protein and results in PDCD5 nuclear translocation PMID:19308289 PDCD5 levels increase significantly on DNA damage in U2OS cells |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: PDCD5 is found in the cytosol under basal conditions and translocates to the nucleus upon DNA damage or genotoxic stress. The cytosolic localization represents its resting state location [PMID:28051100]. This dual localization is consistent with its function as a stress-responsive signaling molecule. Reason: Cytosolic localization is the default location for PDCD5 in unstressed cells. Upon phosphorylation at Ser-119, PDCD5 translocates to the nucleus for its pro-apoptotic function. Supporting Evidence: PMID:28051100 PDCD5 phosphorylation is maintained at a low level in the absence of genotoxic stress |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | UNDECIDED | Summary: This annotation is derived from InterPro domain mapping (PDCD5-like domain, dsDNA_bind PF01984). While the structural similarity suggests potential DNA binding capability, there is limited direct experimental evidence for PDCD5 DNA binding activity in primary literature. The deep research report notes that "Structural and domain annotations... were not retrievable within the 2023-2024 sources." Reason: The annotation is based on domain homology but lacks direct experimental validation. PDCD5 functions primarily through protein-protein interactions (with Tip60, p53, MDM2, FOXP3, CCT) rather than direct DNA binding. The ChIP experiment in PMID:22914926 shows PDCD5 association at the p21 promoter, but this may be indirect through p53 binding rather than direct DNA binding. |
| GO:0005515 protein binding | IPI PMID:19308289 PDCD5 interacts with Tip60 and functions as a cooperator in ... | MODIFY | Summary: This annotation indicates PDCD5 binds to Tip60 (Q92993). PMID:19308289 demonstrates that "PDCD5 binds to Tip60 and enhances the stability of Tip60 protein" and "The binding amount of PDCD5 and Tip60 is significantly increased after UV irradiation." Reason: While the interaction with Tip60 is valid and experimentally demonstrated, the generic 'protein binding' term is uninformative. PDCD5 functions as a Tip60 coactivator, enhancing its acetyltransferase activity. A more specific term should be used. Proposed replacements: acetyltransferase activator activity Supporting Evidence: PMID:19308289 PDCD5 enhances HAT activity of Tip60 and Tip60-dependent histone acetylation in both basal and UV-induced levels |
| GO:0005634 nucleus | IDA PMID:19308289 PDCD5 interacts with Tip60 and functions as a cooperator in ... | ACCEPT | Summary: Direct experimental evidence from PMID:19308289 showing nuclear localization. The study demonstrates co-localization with Tip60 in the nucleus and increased nuclear PDCD5 after DNA damage. Reason: Primary experimental data demonstrating nuclear localization. This is consistent with PDCD5's function in the p53 pathway and DNA damage response. Supporting Evidence: PMID:19308289 PDCD5 levels increase significantly on DNA damage in U2OS cells, as does Tip60 |
| GO:0006915 apoptotic process | IEA GO_REF:0000043 | MODIFY | Summary: This annotation is derived from the UniProt keyword "Apoptosis" (KW-0053). PDCD5 is indeed involved in apoptosis, as extensively documented in primary literature. It was originally cloned as an apoptosis-related gene [PMID:9920759] and promotes apoptosis through the p53/Tip60 pathway [PMID:19308289, PMID:22914926]. Reason: The annotation is correct but too general. PDCD5 specifically promotes apoptosis rather than just being "involved in" it. The more specific term GO:0043065 (positive regulation of apoptotic process) or GO:1902255 (positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator) better captures its function. Proposed replacements: positive regulation of apoptotic process |
| GO:0140311 protein sequestering activity | IDA PMID:19308289 PDCD5 interacts with Tip60 and functions as a cooperator in ... | ACCEPT | Summary: This annotation relates to PDCD5's function in sequestering proteins. According to PMID:19308289, PDCD5 binds Tip60 and stabilizes it. From PMID:22914926, PDCD5 binds p53 and antagonizes MDM2-mediated p53 degradation by "dissociating the interaction between p53 and Mdm2." Reason: PDCD5 does function to sequester/stabilize binding partners (Tip60, p53) away from degradation pathways. It prevents MDM2 from binding p53 by directly interacting with both proteins. Supporting Evidence: PMID:22914926 PDCD5 could dissociate the interaction between p53 and Mdm2 and interact with Mdm2 directly to promote its degradation |
| GO:1901798 positive regulation of signal transduction by p53 class mediator | IMP PMID:19308289 PDCD5 interacts with Tip60 and functions as a cooperator in ... | ACCEPT | Summary: PMID:19308289 demonstrates that PDCD5 enhances p53 signaling through Tip60-mediated K120 acetylation of p53 and participates in p53-dependent expression of pro-apoptotic genes like Bax. Knockdown of PDCD5 impairs p53-dependent apoptosis. Reason: This represents a core function of PDCD5. The protein positively regulates p53 signaling at multiple levels: stabilizing p53 protein, enhancing p53 acetylation via Tip60, and promoting p53-dependent gene transcription. Supporting Evidence: PMID:19308289 PDCD5 increases Tip60-dependent K120 acetylation of p53 and participates in the p53-dependent expression of apoptosis-related genes, such as Bax |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: This annotation is from high-throughput binary protein interactome mapping (HuRI). The interacting partners listed include PICK1 (Q9NRD5), RAD18 (Q9NS91), and TRIM35 (Q9UPQ4-2). These are from a systematic screen rather than hypothesis-driven studies. Reason: High-throughput interactome studies often identify many interactions. While these interactions may be real, the generic 'protein binding' term provides no functional insight. The biological significance of PDCD5 interactions with PICK1, RAD18, or TRIM35 has not been characterized in follow-up studies. |
| GO:0005634 nucleus | IDA PMID:22914926 PDCD5 interacts with p53 and functions as a positive regulat... | ACCEPT | Summary: PMID:22914926 confirms nuclear localization through co-localization assays and shows PDCD5 associates with p53 at the p21 promoter by ChIP. This study provides independent confirmation of nuclear localization. Reason: Multiple lines of evidence confirm nuclear localization. This study adds ChIP data showing PDCD5 at chromatin in the nucleus. Supporting Evidence: PMID:22914926 chromatin immunoprecipitation assays showed an up-regulated association of PDCD5 at the p53BS2 site of the p21 promoter during DNA damage |
| GO:0005634 nucleus | IDA PMID:28051100 Protein serine/threonine phosphatase PPEF-1 suppresses genot... | ACCEPT | Summary: PMID:28051100 demonstrates nuclear localization by immunofluorescence and shows that phosphorylation at Ser-119 promotes nuclear translocation. PPEF-1 dephosphorylates PDCD5 and prevents nuclear accumulation. Reason: This study provides mechanistic insight into how PDCD5 nuclear localization is regulated by phosphorylation status. Supporting Evidence: PMID:28051100 ET treatment rapidly induced nuclear accumulation of PDCD5... Wild-type PPEF-1 completely abrogated PDCD5 stabilization in response to ET |
| GO:0042110 T cell activation | IPI PMID:24012345 PDCD5 negatively regulates autoimmunity by upregulating FOXP... | MODIFY | Summary: PMID:24012345 shows PDCD5 interacts with FOXP3 (Q9BZS1) in T cells. The study demonstrates that PDCD5 enhances FOXP3 function, increases Treg cell frequency, and suppresses Th17/Th1 responses. However, the annotation suggests PDCD5 promotes T cell activation, which is the opposite of what the paper shows. Reason: The annotation is misleading. PDCD5 does not promote T cell activation but rather suppresses it by enhancing regulatory T cell (Treg) function and inhibiting effector T cell responses. A term related to Treg regulation would be more appropriate. Proposed replacements: regulatory T cell differentiation Supporting Evidence: PMID:24012345 PDCD5 negatively regulates autoimmunity by upregulating FOXP3(+) regulatory T cells and suppressing Th17 and Th1 responses |
| GO:0140311 protein sequestering activity | IDA PMID:22914926 PDCD5 interacts with p53 and functions as a positive regulat... | ACCEPT | Summary: PMID:22914926 demonstrates that PDCD5 binds p53 and sequesters it from MDM2-mediated degradation. PDCD5 also directly interacts with MDM2 to promote its degradation. Reason: Protein sequestering activity accurately describes PDCD5's mechanism of protecting p53 from MDM2. Supporting Evidence: PMID:22914926 PDCD5 enhanced the stability of p53 by antagonizing Mdm2-induced p53 ubiquitination, nuclear export and proteasomal degradation |
| GO:1901798 positive regulation of signal transduction by p53 class mediator | IMP PMID:22914926 PDCD5 interacts with p53 and functions as a positive regulat... | ACCEPT | Summary: PMID:22914926 provides extensive IMP evidence for PDCD5 positive regulation of p53 signaling. Knockdown of PDCD5 decreases p53 phosphorylation and p21 expression, while PDCD5 is required for G1 arrest during DNA damage. Reason: Core function of PDCD5. This study provides complementary evidence to PMID:19308289. Supporting Evidence: PMID:22914926 knockdown of PDCD5 by RNA interference decreased the p53 phosphorylation at Ser9, 20 and 392 residues, as well as the expression of p21 protein |
| GO:1902255 positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator | ISS GO_REF:0000024 | ACCEPT | Summary: This ISS annotation is transferred from mouse PDCD5 (UniProtKB:P56812) based on sequence similarity. The term is highly specific and consistent with PDCD5's function in promoting p53-mediated apoptosis through the intrinsic (mitochondrial) pathway. Reason: The annotation is consistent with PDCD5's established function. PMID:16374546 shows PDCD5 is involved in cytochrome c release and Bax translocation to mitochondria, which are hallmarks of the intrinsic apoptotic pathway. Supporting Evidence: PMID:16374546 Suppressed expression of PDCD5 attenuates the release of cytochrome c from mitochondria to cytosol induced by Bax overexpression |
| GO:0042981 regulation of apoptotic process | IMP PMID:16374546 Short interfering RNA against the PDCD5 attenuates cell apop... | MODIFY | Summary: PMID:16374546 demonstrates that siRNA knockdown of PDCD5 attenuates apoptosis and caspase-3 activity induced by Bax overexpression. The paper shows PDCD5 modulates Bax translocation and cytochrome c release. Reason: While accurate, this term is less specific than the evidence supports. PDCD5 specifically promotes apoptosis (positive regulation), not merely regulates it in an unspecified direction. Proposed replacements: positive regulation of apoptotic process Supporting Evidence: PMID:16374546 The programmed cell death 5 (PDCD5) protein plays an important apoptosis-accelerating role in cells undergoing apoptosis |
| GO:0005737 cytoplasm | HDA PMID:16791210 Dynamic proteomics in individual human cells uncovers widesp... | ACCEPT | Summary: This high-throughput localization study (PMID:16791210) used YFP-tagged proteins to systematically study nuclear protein dynamics. The detection of PDCD5 in cytoplasm is consistent with its known cytosol-to-nucleus translocation pattern. Reason: While HDA evidence is lower quality than IDA, the cytoplasmic localization is consistent with extensive literature showing PDCD5 in cytosol under basal conditions. Supporting Evidence: PMID:28051100 PDCD5 protein is maintained at a low level in the absence of genotoxic stress response |
| GO:0010698 acetyltransferase activator activity | IDA PMID:24012345 PDCD5 negatively regulates autoimmunity by upregulating FOXP... | ACCEPT | Summary: PMID:24012345 shows PDCD5 "increases acetylation of FOXP3 in synergy with Tip60." This is consistent with earlier work (PMID:19308289) showing PDCD5 enhances Tip60 HAT activity. PDCD5 acts as a coactivator for Tip60-mediated acetylation. Reason: Core molecular function of PDCD5. It enhances the acetyltransferase activity of Tip60 on multiple substrates including p53 and FOXP3. Supporting Evidence: PMID:24012345 PDCD5 interacts with FOXP3, increases acetylation of FOXP3 in synergy with Tip60 PMID:19308289 PDCD5 enhances HAT activity of Tip60 |
| GO:0071560 cellular response to transforming growth factor beta stimulus | IDA PMID:24012345 PDCD5 negatively regulates autoimmunity by upregulating FOXP... | KEEP AS NON CORE | Summary: PMID:24012345 demonstrates that naive CD4+ T cells from PDCD5 transgenic mice are "more sensitive to TGF-beta-induced Treg polarization and expansion." This indicates PDCD5 modulates the cellular response to TGF-beta. Reason: This is a genuine function but represents a context-specific role in T cells rather than the core molecular function of PDCD5 (which is p53/Tip60 pathway regulation). The TGF-beta response relates to PDCD5's role in Treg differentiation. Supporting Evidence: PMID:24012345 NaΓ―ve CD4(+) T cells from PDCD5tg mice were more sensitive to TGF-Ξ²-induced Treg polarization and expansion |
| GO:0005515 protein binding | IPI PMID:24012345 PDCD5 negatively regulates autoimmunity by upregulating FOXP... | MODIFY | Summary: This annotation indicates PDCD5 binds FOXP3 (Q9BZS1). PMID:24012345 demonstrates that "PDCD5 interacts with FOXP3" through biochemical assays. Reason: The generic 'protein binding' term is uninformative. PDCD5 functions as a FOXP3 coactivator, enhancing FOXP3 acetylation and stability. A more specific functional term should be used. Proposed replacements: acetyltransferase activator activity Supporting Evidence: PMID:24012345 PDCD5 interacts with FOXP3, increases acetylation of FOXP3 in synergy with Tip60 and enhances the repressive function of FOXP3 |
| GO:0005634 nucleus | IDA PMID:24012345 PDCD5 negatively regulates autoimmunity by upregulating FOXP... | ACCEPT | Summary: Another independent IDA confirmation of nuclear localization from PMID:24012345. Reason: Multiple IDA annotations for nuclear localization from different labs confirm this is a well-established location for PDCD5 function. |
| GO:0048487 beta-tubulin binding | IPI PMID:24375412 Programmed cell death protein 5 interacts with the cytosolic... | ACCEPT | Summary: PMID:24375412 demonstrates that "PDCD5 formed a complex with CCT and beta-tubulin" and specifically inhibits beta-tubulin folding. The interaction was mapped by cryo-EM to the CCTbeta apical domain. Reason: The beta-tubulin binding is experimentally validated and functionally significant. It provides a mechanism for PDCD5's anti-proliferative effects through inhibition of tubulin folding. Supporting Evidence: PMID:24375412 PDCD5 formed a complex with CCT and beta-tubulin, a key CCT-folding substrate, and specifically inhibited beta-tubulin folding |
| GO:1903333 negative regulation of protein folding | IMP PMID:24375412 Programmed cell death protein 5 interacts with the cytosolic... | KEEP AS NON CORE | Summary: PMID:24375412 shows PDCD5 inhibits beta-tubulin folding by binding to the CCT chaperonin and sterically interfering with substrate access. Reason: This is a validated function but represents a distinct mechanism from PDCD5's primary role in p53/Tip60 pathway regulation. It may contribute to PDCD5's anti-proliferative effects but is not its core function in apoptosis. Supporting Evidence: PMID:24375412 PDCD5 might exert its apoptotic function at least in part through inhibition of beta-tubulin folding |
| GO:0005515 protein binding | IPI PMID:24375412 Programmed cell death protein 5 interacts with the cytosolic... | MODIFY | Summary: This annotation indicates PDCD5 binds CCT5/TCP-1 epsilon (P48643). The interaction was characterized by proteomics and cryo-EM. Reason: Generic 'protein binding' is uninformative. The interaction with CCT has a specific functional consequence (inhibition of beta-tubulin folding). Proposed replacements: chaperone binding Supporting Evidence: PMID:24375412 A proteomics search for binding partners of phosducin-like protein, a co-chaperone for the cytosolic chaperonin containing tailless complex polypeptide 1 (CCT), revealed a robust interaction between PDCD5 and CCT |
| GO:0008201 heparin binding | IDA PMID:17165023 Studies on interactions of programmed cell death 5 (PDCD5) a... | MARK AS OVER ANNOTATED | Summary: PMID:17165023 uses capillary zone electrophoresis to demonstrate PDCD5-heparin interaction with a binding constant of 4.17 x 10^4 M^-1. However, the biological significance of this interaction is unclear. Reason: While the biochemical interaction is documented, the physiological relevance of PDCD5 binding to heparin is not established. This appears to be an in vitro finding without clear in vivo significance. The paper is primarily a methods paper for CZE analysis. Supporting Evidence: PMID:17165023 The binding constant of the interaction between PDCD5 and heparin was calculated as 4.17 x 10(4) M(-1) by Scatchard analysis |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: High-throughput detection of PDCD5 in B-cell exosomes. The biological significance of exosomal PDCD5 is not characterized. Reason: While the localization in exosomes may be real (HDA evidence from proteomics), this does not represent a functional location for PDCD5's characterized activities. It may represent secretion/clearance rather than active function. |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:9920759 TFAR19, a novel apoptosis-related gene cloned from human leu... | ACCEPT | Summary: This is the original paper identifying PDCD5 (TFAR19). It shows overexpression of PDCD5 "enhances apoptosis triggered by growth factor or serum deprivation" in tumor cells. This established PDCD5 as a pro-apoptotic factor. Reason: This is the foundational paper for PDCD5 function. Positive regulation of apoptosis is the core function of PDCD5, extensively validated by subsequent studies. Supporting Evidence: PMID:9920759 Overexpression of TFAR19 in tumor cells enhances apoptosis triggered by growth factor or serum deprivation |
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Download this section (compressed HTML)Q: What is the structural basis for PDCD5's dual functions in Tip60 activation and CCT inhibition?
Q: Is the heparin binding activity physiologically relevant?
Q: What determines whether PDCD5 promotes p53 stabilization vs. its role in Treg function?
Experiment: ChIP-seq for PDCD5 to determine genome-wide chromatin binding. This would clarify whether PDCD5 has DNA binding activity or only associates with chromatin indirectly through p53.
Hypothesis: PDCD5 associates with chromatin indirectly through p53 rather than via direct DNA binding.
Experiment: Structural studies of PDCD5-Tip60 complex to reveal the molecular mechanism of Tip60 activation by PDCD5.
Hypothesis: PDCD5 binding to Tip60 induces conformational changes that enhance HAT activity.
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