Affinage

KLHL22

Kelch-like protein 22 · UniProt Q53GT1

Length
634 aa
Mass
71.7 kDa
Annotated
2026-06-10
8 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KLHL22 is a BTB-KELCH substrate adaptor for the CUL3 E3 ubiquitin ligase complex that directs K48-linked polyubiquitination and proteasomal degradation of diverse substrates to control cell growth, mitosis, immune homeostasis, and antiviral defense (PMID:29769719, PMID:24067371). Its best-characterized role is nutrient-responsive activation of mTORC1: upon amino acid stimulation, CUL3-KLHL22 ubiquitinates and degrades DEPDC5, a subunit of the GATOR1 complex, relieving GATOR1-mediated inhibition of Rag GTPases and switching on mTORC1 signaling (PMID:29769719). KLHL22 abundance is itself set by UBE4B, which polyubiquitylates and degrades KLHL22; loss of UBE4B raises KLHL22 levels, accelerating DEPDC5 turnover and hyperactivating mTOR, an axis that governs neural precursor proliferation and differentiation during brain development (PMID:36440598). KLHL22 also targets the mitotic kinase PLK1 through bivalent recognition of two motifs independent of PLK1 catalytic activity (PMID:24067371), and limits cell-surface delivery of the immune checkpoint receptor PD-1 by degrading it prior to transport, thereby restraining excessive T cell suppression (PMID:33109719). In an antiviral context, KLHL22 mediates K48-linked degradation of SARS-CoV-2 NSP6, restoring calcium homeostasis and reversing NSP6-induced autophagic cell death (PMID:40373961).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2013 Medium

    Established KLHL22 as a bona fide CUL3 substrate adaptor by identifying its first substrate, defining how it recognizes targets independent of their enzymatic state.

    Evidence Co-IP, kinase-dead PLK1 mutant analysis, and mapping of two distinct interaction motifs within PLK1

    PMID:24067371

    Open questions at the time
    • Functional consequence of PLK1 ubiquitination for mitotic progression not resolved
    • Single lab, no in vivo validation
  2. 2018 High

    Connected KLHL22 to nutrient sensing by showing it degrades DEPDC5 to activate mTORC1, placing the adaptor upstream of a central growth-control hub.

    Evidence Biochemical K48-linked ubiquitination assays, Co-IP, genetic depletion in mammalian cells and C. elegans, xenograft models

    PMID:29769719

    Open questions at the time
    • Mechanism linking amino acid availability to KLHL22 activation not fully defined
    • Subcellular site of DEPDC5 degradation unresolved
  3. 2020 High

    Extended KLHL22 substrate range to immune regulation by demonstrating it degrades PD-1 before surface transport, defining a checkpoint-receptor homeostatic control.

    Evidence Reciprocal Co-IP, KLHL22 loss-of-function causing PD-1 overaccumulation, functional T cell assays

    PMID:33109719

    Open questions at the time
    • Trafficking step at which degradation occurs not precisely mapped
    • In vivo immune phenotype of KLHL22 loss not characterized
  4. 2022 High

    Resolved how KLHL22 itself is regulated, showing UBE4B degrades KLHL22 and that this UBE4B-KLHL22-DEPDC5-mTOR cascade governs neurogenesis.

    Evidence Conditional UBE4B knockout mouse, in vivo ubiquitination assay, genetic epistasis (KLHL22 knockdown rescue), rapamycin rescue

    PMID:36440598

    Open questions at the time
    • Whether UBE4B regulates KLHL22's non-DEPDC5 substrates not addressed
    • Direct biochemical UBE4B-KLHL22 contact not detailed
  5. 2025 Medium

    Implicated KLHL22 in antiviral defense by identifying SARS-CoV-2 NSP6 as a substrate whose degradation restores calcium homeostasis.

    Evidence Co-IP, K48-linked ubiquitination assay, knockdown/overexpression functional assays, calcium measurements

    PMID:40373961

    Open questions at the time
    • Not independently replicated
    • Physiological relevance during authentic infection not established
  6. 2025 Medium

    Linked KLHL22 accumulation to therapy resistance in hepatocellular carcinoma, connecting its dysregulation to a JAK2-PIM1 oncogenic axis.

    Evidence UBE4B siRNA silencing in HCC cells, KLHL22 knockdown epistasis, Western blotting for JAK2/PIM1/LNK, BET inhibitor sensitivity assays

    PMID:40228637

    Open questions at the time
    • Direct KLHL22 substrate driving JAK2-PIM1 changes not identified
    • Single study without replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full substrate repertoire of CUL3-KLHL22 and the signals that switch its activity across tissues remain incompletely defined.
  • No structural model of substrate recognition reported
  • Tissue-specific regulation of adaptor activity unmapped
  • Whether reported cancer phenotypes reflect direct substrate degradation unproven for some studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 2 GO:0060090 molecular adaptor activity 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 1
Partners
CUL3DEPDC5PDCD1PLK1UBE4B
Complex memberships
CUL3-KLHL22 E3 ubiquitin ligase

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 In response to amino acids, CUL3-KLHL22 E3 ubiquitin ligase promotes K48-linked polyubiquitination and degradation of DEPDC5 (an essential subunit of the GATOR1 complex), thereby releasing GATOR1-mediated inhibition of Rag GTPases and activating mTORC1 signaling. Biochemical ubiquitination assays, co-immunoprecipitation, Western blotting, genetic depletion in mammalian cells and C. elegans, xenograft tumor models Nature High 29769719
2020 KLHL22, acting as an adaptor of the CUL3-based E3 ligase complex, mediates K48-linked ubiquitination and degradation of PD-1 before its transport to the cell surface, thereby maintaining PD-1 homeostasis and preventing excessive T cell suppression. Co-immunoprecipitation identifying KLHL22 as a major PD-1-associated protein, genetic depletion (KLHL22 deficiency) leading to PD-1 overaccumulation, Western blotting, functional T cell assays Proceedings of the National Academy of Sciences of the United States of America High 33109719
2013 KLHL22 serves as the BTB-KELCH adaptor in a CUL3 E3-ligase complex that targets the mitotic kinase PLK1 for ubiquitination; PLK1 kinase activity is dispensable for its targeting, and CUL3/KLHL22 contacts two distinct motifs within PLK1, consistent with a bivalent mode of substrate targeting. Co-immunoprecipitation, kinase-dead PLK1 mutant analysis, mapping of interaction motifs within PLK1 Cell cycle (Georgetown, Tex.) Medium 24067371
2022 UBE4B polyubiquitylates and degrades KLHL22; loss of UBE4B causes upregulation of KLHL22 protein levels, which in turn increases DEPDC5 degradation and hyperactivates mTOR, leading to defective neural precursor cell proliferation and differentiation. Suppression of KLHL22 reverses mTOR hyperactivation caused by UBE4B deletion. Conditional UBE4B knockout mouse model, Western blotting, in vivo ubiquitination assay, genetic epistasis (KLHL22 knockdown rescuing UBE4B-deletion phenotype), rapamycin rescue experiments Development (Cambridge, England) High 36440598
2025 KLHL22 is the E3 ubiquitin ligase responsible for K48-linked ubiquitination and degradation of SARS-CoV-2 NSP6, restoring intracellular calcium homeostasis and reversing NSP6-induced autophagic cell death. Co-immunoprecipitation identifying KLHL22–NSP6 interaction, ubiquitination assay demonstrating K48-linked ubiquitination, genetic knockdown/overexpression functional assays, calcium level measurements Journal of advanced research Medium 40373961
2025 In hepatocellular carcinoma, KLHL22 accumulates when UBE4B is deleted (consistent with UBE4B-mediated degradation of KLHL22); elevated KLHL22 drives resistance to BET inhibitors through a JAK2-PIM1 axis involving downregulation of the JAK2 negative regulator LNK. UBE4B siRNA silencing in HCC cells, KLHL22 knockdown epistasis experiment, Western blotting for JAK2/PIM1/LNK, BETi sensitivity assays Biochemical pharmacology Medium 40228637
2020 KLHL22 knockdown in colorectal cancer cells activates the Wnt/β-catenin signaling pathway, partially via regulation of GSK-3β activity and PI3K levels, promoting epithelial-to-mesenchymal transition (EMT) and proliferation. Transwell invasion, MTT assay, Western blotting for Wnt/β-catenin pathway components, xenograft tumor model Cancer management and research Low 32547233

Source papers

Stage 0 corpus · 8 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing. Nature 110 29769719
2020 KLHL22 maintains PD-1 homeostasis and prevents excessive T cell suppression. Proceedings of the National Academy of Sciences of the United States of America 70 33109719
2013 CUL3 and protein kinases: insights from PLK1/KLHL22 interaction. Cell cycle (Georgetown, Tex.) 19 24067371
2020 KLHL22 Regulates the EMT and Proliferation in Colorectal Cancer Cells in Part via the Wnt/β-Catenin Signaling Pathway. Cancer management and research 15 32547233
2022 Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development. Development (Cambridge, England) 7 36440598
2020 KLHL22 promotes malignant melanoma growth in vitro and in vivo by activating the PI3K/Akt/mTOR signaling pathway. Neoplasma 6 32484697
2025 NSP6 regulates calcium overload-induced autophagic cell death and is regulated by KLHL22-mediated ubiquitination. Journal of advanced research 2 40373961
2025 UBE4B modulates BET inhibitor sensitivity via KLHL22-JAK2-PIM1 axis in hepatocellular carcinoma. Biochemical pharmacology 1 40228637

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