YPEL5

YPEL5 is a conserved eukaryotic protein that operates both as a regulatory subunit of the CTLH/GID E3 ubiquitin ligase and as a cell cycle-associated factor at microtubule-organizing structures (PMID:20580816, PMID:38759627). Within the CTLH complex, YPEL5 is retained through WDR26, and its N-terminus mimics the NMNAT1 degron to competitively block WDR26-mediated NMNAT1 ubiquitylation and turnover, an inhibitory mechanism resolved by cryo-EM of NMNAT1- and YPEL5-bound WDR26-CTLH assemblies (PMID:38759627, PMID:38575527). The same basic pocket in YPEL5 can instead serve as a substrate-recruitment surface, engaging acidic-degron proteins when bridged by a sulfinic acid-containing molecular glue that drives cooperative binding of CTLH E3 to BET-family proteins (PMID:41942733). Independently, YPEL5 localizes dynamically through the cell cycle—to the nucleus and centrosome in interphase and to spindle poles, the spindle midzone, and the midbody during mitosis and cytokinesis—and its depletion impairs proliferation and embryonic development (PMID:20580816, PMID:15556292). YPEL5 also negatively regulates innate immunity by physically interacting with IKBKE and functionally with TBK1 to restrain IFNB1 production (PMID:27705791), and acts in vivo as a metabolic and developmental regulator: zebrafish ypel5 controls hepatic metabolism through a PPARα–Hnf4a axis (PMID:36948605), while oocyte-specific loss in mice causes female infertility with defective folliculogenesis, spindle assembly, and mitochondrial homeostasis (PMID:42086779).

1. 2004 Medium

   Established the basic cell-biological behavior of YPEL5 by showing it occupies distinct subcellular sites across the cell cycle, separating it from the YPEL1-4 paralogs.

   Evidence Indirect immunofluorescence in COS-7 cells

   PMID:15556292

   Open questions at the time

   • No functional consequence of localization tested
   • No interacting partners identified
2. 2010 High

   Connected YPEL5 localization to function, demonstrating that loss disrupts cell cycle progression and development, and identified its first physical partners.

   Evidence Immunofluorescence and siRNA/morpholino knockdown in COS-7 cells and medaka embryos; yeast two-hybrid screen identifying RanBPM (RANBP9) and RanBP10

   PMID:20580816

   Open questions at the time

   • RANBP9/RANBP10 interaction is yeast two-hybrid only, not validated in mammalian cells
   • Mechanism linking localization to proliferation undefined
3. 2013 Medium

   Documented a YPEL5/PPP1CB RNA chimera in CLL, raising the possibility that the locus contributes to malignancy, though the functional defect mapped to truncated PPP1CB rather than YPEL5.

   Evidence Transcriptome sequencing, phosphatase assays, and siRNA proliferation readouts in CLL cell lines

   PMID:23382248

   Open questions at the time

   • Functional consequence attributed to PPP1CB truncation, not YPEL5
   • Chimera later reported not to be CLL-specific
4. 2016 Medium

   Defined a signaling role for YPEL5 as a negative regulator of innate immunity through direct association with the non-canonical IKK kinase machinery.

   Evidence Reciprocal co-IP with IKBKE and siRNA knockdown with IFNB1 induction and TBK1/IKBKE phosphorylation readouts in HEK293T and macrophage lines

   PMID:27705791

   Open questions at the time

   • Single lab
   • Whether this depends on CTLH complex membership not addressed
   • No structural basis for IKBKE binding
5. 2017 Medium

   Demonstrated cross-species functional conservation by showing human YPEL5 substitutes for yeast Moh1 in DNA-damage-induced apoptosis.

   Evidence Functional complementation of moh1Δ yeast with human YPEL5 and apoptosis readouts

   PMID:28173693

   Open questions at the time

   • Pro-apoptotic mechanism in human cells not defined
   • Molecular partners in apoptosis unknown
6. 2021 Medium

   Placed YPEL5 expression under m6A epigenetic control and tied its overexpression to suppression of proliferation markers in cancer cells.

   Evidence m6A-seq, METTL3 knockdown/overexpression, YTHDF2 studies, and YPEL5 overexpression with CCNB1/PCNA readouts in colorectal cancer cells

   PMID:33411363

   Open questions at the time

   • Direct mechanism linking YPEL5 to CCNB1/PCNA reduction unknown
   • Single lab
7. 2023 High

   Established an in vivo metabolic function, defining a PPARα→Hnf4a regulatory axis through which YPEL5 controls hepatic metabolism and proliferation.

   Evidence CRISPR/Cas9 ypel5 knockout in zebrafish with metabolomics, transcriptomics, and hnf4a overexpression rescue

   PMID:36948605

   Open questions at the time

   • How YPEL5 protein activates PPARα signaling mechanistically unclear
   • Connection to CTLH E3 function not addressed
8. 2024 High

   Resolved YPEL5's defining biochemical role as a CTLH E3 subunit whose N-terminal degron mimicry competitively inhibits WDR26-mediated NMNAT1 ubiquitylation, and showed WDR26 is required to retain YPEL5 in the complex.

   Evidence Cryo-EM structures, in vitro ubiquitylation and cellular turnover assays with degron mutagenesis; complementation in CTLH-deficient cells with WDR26 disease mutants

   PMID:38575527 PMID:38759627

   Open questions at the time

   • Full repertoire of substrates antagonized by YPEL5 unknown
   • Whether degron mimicry operates on substrates other than NMNAT1 untested
9. 2024 Medium

   Connected the CTLH-resident YPEL5 to host defense, showing its loss enhances anti-bacterial activity through GABAergic signaling, AMPK activation, and autophagy.

   Evidence Genome-wide CRISPR screen and CRISPR knockout macrophages with intracellular bacterial growth and cell death readouts

   PMID:39472457

   Open questions at the time

   • YPEL5-specific contribution within the complex not isolated
   • Direct substrate driving the antimicrobial phenotype not identified
10. 2026 High

    Revealed a substrate-recruitment capacity for YPEL5 distinct from its inhibitory role, showing its basic pocket can engage acidic degrons and be co-opted by a molecular glue to recruit BET proteins for degradation.

    Evidence Cryo-EM/structural determination, biochemical binding, and cellular degradation assays with molecular glue ZZ1

    PMID:41942733

    Open questions at the time

    • Endogenous acidic-degron substrates recruited by the basic pocket unknown
    • Physiological versus glue-induced recruitment not distinguished
11. 2026 Medium

    Demonstrated an essential in vivo role in reproduction, with oocyte-specific loss causing infertility through follicle depletion, DNA damage, oxidative stress, and spindle/mitochondrial defects.

    Evidence Oocyte-specific conditional knockout mouse with folliculogenesis, DNA damage, mitochondrial, and spindle imaging readouts

    PMID:42086779

    Open questions at the time

    • No epistasis rescue to assign causality
    • Whether phenotype reflects CTLH E3 function or its mitotic localization role untested

• How YPEL5's distinct activities—CTLH-resident ubiquitylation control, mitotic localization, innate-immune signaling, and metabolic/reproductive regulation—are integrated within a single protein remains unresolved.
• No unified model linking complex membership to localization-dependent roles
• Endogenous substrate spectrum incompletely defined
• Mechanistic basis of IKBKE and PPARα regulation not structurally resolved