Affinage

Showing PIWIL2 — MILI is a alias.

PIWIL2

Piwi-like protein 2 · UniProt Q8TC59

Length
973 aa
Mass
109.8 kDa
Annotated
2026-06-10
98 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIWIL2 (MILI) is a PIWI-clade Argonaute endonuclease that binds piRNAs and silences transposable elements in the germline, and that has been co-opted into multiple pro-survival and tumorigenic signaling pathways in somatic and cancer cells (PMID:16751777, PMID:17446352, PMID:16377660). In germ cells it binds a distinct class of 26–31 nt piRNAs with 5' uridine bias, recognizing the 2-nt 3' overhang of small RNAs through a canonical PAZ-domain fold (PMID:16751777, PMID:33774220). Its DDH catalytic triad drives the endonucleolytic 'ping-pong' loop that generates secondary piRNA 5' ends, and this activity is selectively required to silence LINE-1 retrotransposons and to direct de novo DNA methylation of LINE-1 and IAP regulatory regions in fetal germ cells (PMID:17446352, PMID:18381894, PMID:22020280). MILI is anchored to the intermitochondrial cement for piRNA biogenesis by GASZ, and assembles effector complexes via symmetrically dimethylated N-terminal arginines recognized by TDRD1, with TEX15 acting as a downstream nuclear effector of transposon DNA methylation (PMID:19465913, PMID:32381626, PMID:41063345). Loss of MILI blocks spermatogenesis at early prophase I and impairs germline stem-cell self-renewal, with the protein additionally associating with translation initiation factors eIF3a and the eIF4E/4G cap-binding complex to promote translation; a human loss-of-function frameshift variant causes Sertoli cell-only syndrome (PMID:14736746, PMID:19114715, PMID:36153567). Beyond the germline, PIWIL2 functions in adult hippocampal neurogenesis and acts as a guide for somatic piRNAs that post-transcriptionally silence transcripts such as FTH1 and maintain colonic transposon repression (PMID:36472244, PMID:30102404, PMID:40789164). In tumor cells PIWIL2 promotes survival and proliferation through a recurring strategy of binding and stabilizing signaling proteins: it forms a PIWIL2/STAT3/c-Src complex that represses p53 and induces Bcl-XL, binds IKK to activate NF-κB while restraining autophagy, stabilizes β-catenin to upregulate CyclinD1, stabilizes HDAC3 against Siah2-mediated degradation, suppresses TGF-β signaling by disrupting the Hsp90–TβR complex, and modulates microtubule dynamics through TBCB (PMID:16377660, PMID:22303479, PMID:22848678, PMID:28393858, PMID:29555935, PMID:31262447, PMID:33469229).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2004 High

    Established that MILI is genetically required for the germline, defining its core biological context before any molecular activity was known.

    Evidence Targeted knockout in mice with co-IP of MILI and MVH

    PMID:14736746

    Open questions at the time
    • Did not define the molecular activity underlying the arrest
    • MVH interaction not mechanistically dissected
  2. 2006 High

    Identified the RNA ligands of MILI, revealing it as a piRNA-binding protein and defining a new small-RNA class.

    Evidence Small RNA cloning/sequencing from MILI immunoprecipitates of mouse testes

    PMID:16751777

    Open questions at the time
    • Did not establish catalytic mechanism
    • Function of piRNAs not yet demonstrated
  3. 2007 High

    Showed that MILI catalyzes piRNA 5'-end formation and silences retrotransposons, linking the piRNA pathway to genome defense and DNA methylation.

    Evidence piRNA deep sequencing, retrotransposon expression, and bisulfite sequencing in Mili mutants

    PMID:17446352

    Open questions at the time
    • Did not prove which catalytic residues were essential
    • Did not separate ping-pong from methylation roles
  4. 2008 High

    Placed MILI in fetal de novo DNA methylation of retrotransposons alongside MIWI2 and showed stage-specific piRNA populations.

    Evidence Bisulfite sequencing and piRNA profiling in MILI-null and MIWI2-null fetal germ cells

    PMID:18381894

    Open questions at the time
    • Nuclear effectors connecting piRNAs to methylation machinery unidentified
  5. 2008 High

    Defined a non-silencing germline role for MILI in stem-cell self-renewal and translation, broadening its function beyond TE control.

    Evidence Mili-null analysis, co-IP with eIF3a/eIF4E/eIF4G, protein synthesis measurement in seminiferous tubules

    PMID:19114715

    Open questions at the time
    • Direct mRNA targets of translational regulation not defined
    • Relation to piRNA function unclear
  6. 2009 High

    Identified TDRD1 as a methylarginine-dependent partner of MILI required for proper piRNP composition and downstream MIWI2 localization.

    Evidence Complex purification/MS, methylarginine recognition assays, and Tdrd1-null genetics with piRNA profiling

    PMID:19345100 PMID:19465913

    Open questions at the time
    • Mechanism by which TDRD1 ensures piRNP fidelity not fully resolved
  7. 2011 High

    Proved catalytic activity is essential in vivo and selectively required for LINE-1 silencing, separating substrate-specific functions of MILI.

    Evidence Mili-DAH catalytic knock-in mice with piRNA sequencing and fertility analysis

    PMID:22020280

    Open questions at the time
    • Why IAP silencing is catalysis-independent not explained
  8. 2011 Medium

    Revealed a somatic, piRNA-independent role for MILI in genotoxic DNA repair via chromatin relaxation and histone acetylation.

    Evidence Mili-KO MEFs with chromatin relaxation, H3-acetylation, and multiple DNA repair assays

    PMID:21310163 PMID:22110608

    Open questions at the time
    • Molecular link between MILI and p300/HAT activity not defined
    • Whether piRNAs participate not established
  9. 2012 High

    Mapped the in vivo primary piRNA biogenesis pathway, showing MILI-bound precursors are processed by distinct nucleolytic activities.

    Evidence MILI HITS-CLIP and RNA-seq in postnatal mouse testis

    PMID:22842725

    Open questions at the time
    • Identity of the processing nucleases not fully resolved here
  10. 2012 Medium

    Demonstrated that human PIWIL2 acquires oncogenic signaling functions, anchoring STAT3/c-Src to repress p53 and suppressing TGF-β signaling.

    Evidence Co-IP, PAZ/PIWI domain mapping, reporter assays, and TβR degradation assays in human cells

    PMID:22303479 PMID:22848678

    Open questions at the time
    • Single-lab studies
    • Whether piRNA binding is required for these protein-protein functions unclear
  11. 2017 Medium

    Extended the recurring 'stabilize a signaling partner' theme to circadian and antiviral contexts, showing PIWIL2 suppresses BMAL1/CLOCK and inhibits HIV via tRNA binding.

    Evidence Co-IPs, E-Box ChIP, circadian reporters, and tRNA RIP with antisense validation

    PMID:28331090 PMID:28903391

    Open questions at the time
    • Complex multi-step pathway claims rest on single studies
    • tRNA-based antiviral mechanism not independently confirmed
  12. 2020 Medium

    Identified TEX15 as a nuclear effector linking MILI piRNPs to TE DNA methylation independent of piRNA production.

    Evidence Co-IP of TEX15 with MILI, Tex15 mutant analysis, piRNA and methylation profiling

    PMID:32381626

    Open questions at the time
    • How TEX15 directs methylation machinery to target loci unknown
    • Single lab
  13. 2021 Medium

    Resolved the structural basis of piRNA 3'-end recognition and extended the somatic oncogenic network to NF-κB activation and autophagy suppression.

    Evidence X-ray crystallography of the PAZ domain; co-IP of PIWIL2-IKK/TSC1 with xenograft validation

    PMID:33469229 PMID:33774220

    Open questions at the time
    • PAZ recognition not validated by mutagenesis
    • IKK pathway mechanism from a single lab
  14. 2022 Medium

    Established somatic and disease relevance: PIWIL2 supports adult neurogenesis, and human loss-of-function causes Sertoli cell-only syndrome.

    Evidence Hippocampal Mili knockout with RNA-seq; whole-exome sequencing plus hiPSC SSCLC differentiation

    PMID:36153567 PMID:36472244

    Open questions at the time
    • Direct effectors in neurogenesis not defined
    • Single patient for the human variant
  15. 2025 High

    Defined the mitochondrial scaffold that anchors MILI for fetal piRNA biogenesis, identifying GASZ as the direct recruiting factor.

    Evidence Co-IP of GASZ-MILI with conditional interaction disruption at two developmental stages and piRNA/transposon phenotyping

    PMID:41063345

    Open questions at the time
    • Structural basis of GASZ-MILI interaction not resolved
    • Whether GASZ recruits other piRNA factors unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved whether the diverse somatic/oncogenic protein-stabilization functions of PIWIL2 depend on its catalytic piRNA-binding activity or represent piRNA-independent moonlighting, and whether they reflect a unified mechanism.
  • No study links the germline catalytic activity to the tumor signaling roles
  • Most somatic interactions rest on single-lab co-IP
  • No structural model of full-length human PIWIL2 with substrate

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 7 GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0140098 catalytic activity, acting on RNA 2 GO:0003677 DNA binding 1 GO:0045182 translation regulator activity 1
Localization
GO:0005739 mitochondrion 2 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-4839726 Chromatin organization 4 R-HSA-1474165 Reproduction 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-1640170 Cell Cycle 2 R-HSA-9612973 Autophagy 1 R-HSA-9909396 Circadian clock 1
Partners
GASZHDAC3HSP90IKKSTAT3TBCBTDRD1TEX15
Complex memberships
PIWIL2/STAT3/c-Src complexeIF4E/eIF4G cap-binding complex (associated)intermitochondrial cement (piRNA biogenesis)

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 MILI (PIWIL2) binds a novel class of small RNAs (26-31 nt, termed piRNAs) in mouse male germ cells, where they accumulate at the onset of meiosis; piRNAs show strong 5' uridine preference and map to discrete genomic clusters suggesting processing from long primary transcripts. Small RNA cloning and sequencing from MILI immunoprecipitates from mouse testes; genomic mapping of >1000 unique piRNA sequences Nature High 16751777
2004 MILI (PIWIL2) is essential for spermatogenesis; Mili-null mice are male-sterile with spermatogenesis blocked at early prophase I (zygotene to early pachytene). MILI physically binds MVH (an essential early spermatocyte factor), suggesting a functional association in post-transcriptional regulation. Targeted gene knockout in mice; co-immunoprecipitation of MILI and MVH Development (Cambridge, England) High 14736746
2007 MILI (PIWIL2) catalyzes the formation of piRNA 5' ends via an endonucleolytic 'ping-pong' amplification loop. Mili mutants derepress LINE-1 and IAP retrotransposons and lose DNA methylation at LINE-1 regulatory elements, demonstrating a conserved role for MILI in transposon suppression. Deep sequencing of piRNAs from wild-type and Mili mutant testes; analysis of retrotransposon expression; bisulfite sequencing of LINE-1 methylation Science (New York, N.Y.) High 17446352
2008 MILI and MIWI2 are required for de novo DNA methylation of LINE-1 and IAP retrotransposon regulatory regions in fetal male germ cells; loss of either protein impairs this de novo methylation. The piRNA populations in fetal germ cells are distinct from those in neonatal and adult germ cells, and piRNA expression is reduced in both MILI-null and MIWI2-null fetal germ cells. Bisulfite sequencing of retrotransposon regulatory regions in MILI-null and MIWI2-null fetal germ cells; comprehensive piRNA sequencing Genes & development High 18381894
2011 MILI's (PIWIL2) endonuclease activity (DDH catalytic triad) is required for secondary piRNA amplification and is selectively required for LINE-1 (but not IAP) silencing. Point mutation of the second aspartic acid to alanine (Mili-DAH) abolishes transposon piRNA amplification, depletes Miwi2-bound piRNAs, and causes spermatogenic failure. Knock-in point mutation of MILI catalytic residue in mice (Mili-DAH allele); piRNA sequencing; retrotransposon expression analysis; fertility analysis Nature High 22020280
2009 MILI interacts with Tudor domain-containing protein 1 (TDRD1) throughout spermatogenesis. This RNA-independent interaction is promoted by recognition of symmetrically dimethylated arginines at the N-terminus of MILI by TDRD1 Tudor domains. Loss of TDRD1 causes delocalization of MIWI2 from nucleus to cytoplasm, LINE-1 derepression, loss of DNA methylation at L1 regulatory elements, and entry of aberrant transcripts into MILI piRNPs. Purification of MILI-containing complexes from adult mouse testes with mass spectrometry identification of TDRD1; methylarginine recognition assay; MIWI2 localization in Tdrd1-null mice; piRNA profiling Nature structural & molecular biology High 19465913
2009 MILI specifically interacts with TDRD1 through an RNA-independent mechanism mediated by the N-terminal domain of MILI and the N-terminal region of TDRD1 (MYND domain and first two Tudor domains). MILI positively regulates Tdrd1 mRNA expression. Tdrd1 is not required for piRNA biogenesis but is critical for spermatogenesis. Co-immunoprecipitation of MILI and TDRD1 in spermatogenic cells; domain mapping by truncation analysis; Tdrd1-null mouse phenotypic analysis; piRNA sequencing Current biology : CB High 19345100
2008 MILI (PIWIL2) is expressed in the cytoplasm of testicular germ line stem cells and early spermatocytes, enriched in chromatoid bodies. MILI is essential for self-renewing division of germ line stem cells. MILI forms a stable RNA-independent complex with eIF3a and associates with the eIF4E- and eIF4G-containing m7G cap-binding complex, positively regulating translation. Immunofluorescence localization; Mili-null mouse analysis; co-immunoprecipitation with eIF3a, eIF4E, eIF4G; protein synthesis rate measurement in isolated seminiferous tubules The Journal of biological chemistry High 19114715
2012 MILI (PIWIL2) HITS-CLIP defines the in vivo primary piRNA biogenesis pathway in mouse postnatal testis, showing that Mili-bound precursor transcripts are cleaved by distinct nucleolytic activities. Pachytene piRNAs are the end products of RNA processing from Mili-bound precursors. HITS-CLIP (high-throughput sequencing after cross-linking and immunoprecipitation) of MILI from mouse testis; RNA-seq Nature structural & molecular biology High 22842725
2001 MILI (mouse piwi-like) protein contains conserved C-terminal PIWI domain and is expressed in germ cells of adult testis and in primordial germ cells of developing mouse embryos. MIWI possesses RNA binding activity. RT-PCR cloning; in situ hybridization; domain sequence analysis Mechanisms of development Medium 11578866
2005 PIWIL2 expression in NIH-3T3 cells induces high-level expression of anti-apoptotic Bcl-XL, correlated with increased STAT3 expression. siRNA silencing of PIWIL2 suppresses STAT3 and Bcl-XL expression and induces apoptosis. PIWIL2 overexpression induces fibroblast transformation. Overexpression in NIH-3T3 cells; cancer gene array; siRNA knockdown; soft agar transformation assay Human molecular genetics Medium 16377660
2012 Human PIWIL2 (HILI) directly associates with STAT3 protein via its PAZ domain and forms a PIWIL2/STAT3/c-Src triple protein-protein complex. STAT3 is phosphorylated by c-Src and translocated to the nucleus to bind the P53 promoter and repress P53 transcription. Co-immunoprecipitation of PIWIL2-STAT3-c-Src complex; PAZ domain mapping; P53 promoter reporter assay; STAT3 nuclear translocation analysis PloS one Medium 22303479
2015 MILI (PIWIL2) and MIWI2 have distinct roles in DNA methylation of transposable elements: MILI is responsible for DNA methylation of a larger subset of TE families than MIWI2. Miwi2 deficiency had minor impact on piRNA biogenesis but caused overexpression of specific LINE1 families activating the ping-pong piRNA cycle. Analysis of Miwi2-knockout mice; piRNA sequencing; bisulfite sequencing of TE methylation Cell reports High 26279574
2017 In mouse oocytes, MILI (PIWIL2) depletion abolishes almost all piRNAs and is accompanied by increased transcripts from specific retrotransposons (especially IAPs). MILI-null oocytes also lose novel 21-23 nt small RNAs (spiRNAs) with 10-nt complementarity to piRNAs, which are produced MILI-dependently and DICER-independently. Gene knockout analysis of MILI, MIWI, and PLD6 in oocytes; small RNA sequencing Nucleic acids research High 28115634
2019 TDRKH specifically recruits MIWI (but not MILI) to the intermitochondrial cement (IMC) for piRNA processing; TDRKH enables trimming of MILI-bound piRNAs. MILI and MIWI enter the piRNA pathway by separate mitochondrial surface-based scaffolding mechanisms. TDRKH knockout mice; co-immunoprecipitation; piRNA sequencing; immunofluorescence localization of MILI and MIWI at IMC Nucleic acids research Medium 30590800
2020 TEX15 (testis-specific protein) associates with MILI in testis and is required for transposable element silencing. Loss of Tex15 causes TE desilencing with intact piRNA production, identifying TEX15 as a potential nuclear effector of MILI that silences TEs by DNA methylation. Co-immunoprecipitation of TEX15 with MILI from testis; Tex15 mutant analysis; piRNA sequencing; TE expression analysis; DNA methylation profiling Genes & development Medium 32381626
2012 HILI (human PIWIL2) suppresses TGF-β signaling by physically associating with Hsp90 in HEK-293 cells, preventing Hsp90-TβR heteromeric complex formation and promoting ubiquitin/Smurf2-dependent degradation of TGF-β receptors, leading to loss of TGF-β-induced Smad2/3 phosphorylation. Co-immunoprecipitation of HILI with Hsp90; TβR ubiquitination and degradation assays; Smad2/3 phosphorylation western blot PloS one Medium 22848678
2011 Piwil2 (Mili) is required for chromatin relaxation and histone H3 acetylation upon cisplatin treatment; Mili-KO MEFs show defective repair of cisplatin-induced DNA intrastrand crosslinks (Pt-GG), UV-induced cyclobutane pyrimidine dimers, and ionizing radiation-induced double-strand breaks, correlated with H3 hypoacetylation and reduced p300 HAT activity. Mili-KO MEFs; chromatin relaxation assay; histone acetylation western blot; CPD repair assay; Pt-GG repair assay; comet assay for DSBs; apoptosis markers Mutation research Medium 21310163
2011 PIWIL2 (Mili) is required for DNA repair via an axis of PIWIL2 → histone acetylation → chromatin relaxation. Piwil2-deficient MEFs are defective in UV-induced CPD repair, Pt-GG repair, and DSB repair, with increased apoptosis. UV irradiation transiently activates PIWIL2 in normal human fibroblasts. UV irradiation of Mili-KO MEFs and normal human fibroblasts; CPD immunostaining; PARP cleavage and caspase-3 activation; western blot for H3 acetylation PloS one Medium 22110608
2014 PIWIL2 upregulates c-Myc by interacting with NME2 and facilitating NME2 binding to the G4-motif region within the c-Myc promoter. In a c-Myc-mediated manner, PIWIL2 upregulates RhoA, which induces filamentary F-actin. PIWIL2 deficiency blocks c-Myc expression, cell cycle progress, and cell proliferation. Co-immunoprecipitation of PIWIL2-NME2; ChIP for NME2 at c-Myc G4-motif; knockdown experiments; F-actin visualization Oncotarget Medium 25193865
2014 PIWIL2 binds keratin 8 (K8) and p38 through its PIWI domain, forming a PIWIL2/K8/p38 triple complex. This increases K8 Ser-73 phosphorylation and inhibits ubiquitin-mediated K8 degradation, thereby reducing Fas receptor membrane levels and inhibiting Fas-mediated apoptosis. PIWIL2 also represses p53 phosphorylation through p38. Bacterial two-hybrid screening; co-immunoprecipitation; K8 phosphorylation and ubiquitination assays; Fas membrane level analysis; PIWI domain mapping Molecular and cellular biology Medium 25113562
2017 HILI (human PIWIL2) inhibits HIV replication in activated CD4+ T cells. Hili is rapidly induced upon T cell activation. Hili binds to specific tRNA species including rare tRNAs; targeting tRNAArg(UCU) with an antisense oligonucleotide replicated the HIV-inhibitory effect of Hili. Hili also inhibited retrotransposition of IAP by a similar tRNA-based mechanism. Hili depletion in activated CD4+ T cells; viral protein and particle measurement; RNA immunoprecipitation of tRNAs; antisense oligonucleotide targeting of rare tRNAs; IAP retrotransposition assay Journal of virology Medium 28331090
2017 HILI (PIWIL2) inhibits Gigaxonin-mediated TBCB ubiquitination and degradation by interacting with TBCB, promoting HSP90-TBCB binding, suppressing Gigaxonin-TBCB interaction, and reducing PAK1-induced TBCB phosphorylation. This suppresses microtubule polymerization and promotes cell proliferation, migration, and invasion. Co-immunoprecipitation of HILI-TBCB, HSP90-TBCB; ubiquitination assay; microtubule polymerization assay; PAK1 phosphorylation assay Scientific reports Medium 28393858
2018 PIWIL2 interacts with HDAC3, stabilizing it from Siah2-mediated ubiquitin degradation through competitive association. PIWIL2 also facilitates the interaction between HDAC3 and CK2α, promoting CK2α-mediated HDAC3 phosphorylation and enhancing HDAC3 activity. Co-immunoprecipitation of PIWIL2-HDAC3-Siah2 and PIWIL2-HDAC3-CK2α; ubiquitination assay; HDAC3 deacetylase activity assay; phosphorylation assay Cell death & disease Medium 29555935
2017 PIWIL2 suppresses circadian rhythms by activating PI3K-AKT through facilitating SRC binding with PI3K, which deactivates GSK3β by phosphorylation, suppressing GSK3β-induced phosphorylation and degradation of BMAL1 and CLOCK. PIWIL2 also directly binds E-Box sequences associated with the BMAL1/CLOCK complex to negatively regulate transcription of clock-controlled genes. Co-immunoprecipitation of PIWIL2-SRC-PI3K; GSK3β phosphorylation assay; BMAL1/CLOCK stability assays; E-Box binding/ChIP assay; circadian rhythm reporter assays Oncotarget Medium 28903391
2019 PIWIL2 suppresses GSK3β-induced phosphorylation and ubiquitination of β-catenin, increasing β-catenin nuclear accumulation. By stabilizing β-catenin and upregulating CyclinD1, PIWIL2 promotes cell cycle progression and proliferation in tumor cells. Co-immunoprecipitation; β-catenin phosphorylation and ubiquitination assays; nuclear fractionation; cell cycle analysis Biochemical and biophysical research communications Medium 31262447
2021 PIWIL2 directly binds IKK and promotes its phosphorylation, leading to IκB phosphorylation and NF-κB nuclear translocation (anti-apoptotic). PIWIL2 also competitively inhibits IKK binding to TSC1, deactivating the mTORC1 pathway and suppressing ULK1 phosphorylation, thereby blocking autophagy initiation. Co-immunoprecipitation of PIWIL2-IKK and PIWIL2-TSC1; IKK phosphorylation assay; NF-κB nuclear translocation assay; ULK1 phosphorylation assay; mouse xenograft model with IKK dependency test Cell death and differentiation Medium 33469229
2021 Crystal structure of the human PIWIL2 PAZ domain reveals a canonical PAZ fold. PIWIL2 utilizes a deep hydrophobic concave to accommodate the 2-nt 3'-end of RNAs. Recognition of 2-nt 3' overhangs by PIWIL2 is conserved in other human PIWIL proteins. X-ray crystallography of PIWIL2 PAZ domain; homology modeling of PIWIL2 bound to 2-nt 3' overhang Biochemical and biophysical research communications Medium 33774220
2022 Mili (PIWIL2) is essential for neurogenesis in the postnatal mouse hippocampus. Depletion of Mili and piRNAs in the adult hippocampus impairs aNPC differentiation toward a neural fate, induces cellular senescence, and generates reactive glia. Transcripts modulated upon Mili depletion include repetitive elements and mRNAs encoding neurogenesis-essential proteins. Mili knockout in adult mouse hippocampus; RNA sequencing of adult neural progenitor cells; immunofluorescence for senescence markers; neurogenesis quantification EMBO reports Medium 36472244
2022 Homozygous loss-of-function frameshift variant in PIWIL2 (p.His244ArgfsTer31) causes Sertoli cell-only syndrome in a human patient. PIWIL2-null hiPSCs show severely impaired formation and maintenance of spermatogonial stem cell-like cells (SSCLCs) in vitro. Wnt signaling pathway is inactivated in the PIWIL2-null SSCLC induction process. Whole-exome sequencing; in vitro differentiation of PIWIL2-null hiPSCs into germ cell-like cells; RNA-seq; Wnt pathway inhibitor experiments Stem cell research & therapy Medium 36153567
2025 GASZ directly recruits MILI to the intermitochondrial cement (IMC) in prospermatogonia through spermatocytes. Disruption of the GASZ-MILI interaction reduces fetal piRNA levels, increases transposon expression, and compromises spermatogonial and spermatocyte development. Disruption in adulthood impairs steady-state spermatogenesis. Co-immunoprecipitation of GASZ and MILI; conditional disruption of GASZ-MILI interaction in embryonic germ cells and adult mice; piRNA sequencing; immunofluorescence localization at IMC; transposon expression analysis Nucleic acids research High 41063345
2022 Piwil2 regulates CREB2 expression by controlling DNMT3A-mediated DNA methylation of the CREB2 promoter. Downregulation of Piwil2 by hypoxic postconditioning reduces DNMT3A levels, decreasing CREB2 CpG methylation and increasing CREB2 expression, which protects against cerebral ischemia-induced neuronal loss. Antisense oligodeoxynucleotide knockdown of Piwil2; lentiviral overexpression; RNA binding protein immunoprecipitation (RIP) for piRNA identification; DNMT3A western blot; bisulfite sequencing of CREB2 promoter Brain pathology (Zurich, Switzerland) Medium 35794855
2018 Human PIWIL2 (HILI) mediates post-transcriptional knockdown of ferritin heavy chain 1 (FTH1) mRNA via a piRNA (piR-FTH1) through the HIWI2 and HILI pathway in somatic (triple-negative breast cancer) cells. piRNA transfection; FTH1 mRNA and protein level measurement; HILI/HIWI2 depletion; immunoprecipitation of piR-FTH1/PIWIL2 complex Nucleic acids research Medium 30102404
2024 piRNA-4447944 binds PIWIL2 to form a piR-4447944/PIWIL2 complex that inhibits tumor suppressor NEFH through direct interaction at the post-transcriptional level, promoting castration-resistant prostate cancer growth and metastasis. Small RNA sequencing; piRNA overexpression/knockdown; Co-IP of piRNA-4447944 with PIWIL2; NEFH mRNA/protein analysis; in vitro and in vivo functional assays International journal of biological sciences Medium 38993562
2025 PIWIL2 depletion in colon epithelial Caco2 cells leads to decreased non-canonical TE-targeting piRNAs, increased LINE-1 levels and activity, increased anchorage-independent growth, and DNA damage, indicating a tumor-suppressing role of PIWIL2 in the colon through maintenance of TE silencing. PIWIL2 depletion in Caco2 cells; piRNA sequencing; LINE-1 reporter assay; anchorage-independent growth assay; DNA damage markers; bioinformatic SWAN analysis of colon cancer datasets Biology open Medium 40789164

Source papers

Stage 0 corpus · 98 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 A novel class of small RNAs bind to MILI protein in mouse testes. Nature 1192 16751777
2007 Developmentally regulated piRNA clusters implicate MILI in transposon control. Science (New York, N.Y.) 809 17446352
2008 DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. Genes & development 725 18381894
2004 Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development (Cambridge, England) 624 14736746
2011 The endonuclease activity of Mili fuels piRNA amplification that silences LINE1 elements. Nature 283 22020280
2009 Loss of the Mili-interacting Tudor domain-containing protein-1 activates transposons and alters the Mili-associated small RNA profile. Nature structural & molecular biology 226 19465913
2005 Stem-cell protein Piwil2 is widely expressed in tumors and inhibits apoptosis through activation of Stat3/Bcl-XL pathway. Human molecular genetics 224 16377660
2001 Two mouse piwi-related genes: miwi and mili. Mechanisms of development 219 11578866
2012 Mili and Miwi target RNA repertoire reveals piRNA biogenesis and function of Miwi in spermiogenesis. Nature structural & molecular biology 208 22842725
2008 MILI, a PIWI-interacting RNA-binding protein, is required for germ line stem cell self-renewal and appears to positively regulate translation. The Journal of biological chemistry 178 19114715
2009 Mili interacts with tudor domain-containing protein 1 in regulating spermatogenesis. Current biology : CB 140 19345100
2013 The expression of stem cell protein Piwil2 and piR-932 in breast cancer. Surgical oncology 113 23992744
2010 Pathways of proliferation and antiapoptosis driven in breast cancer stem cells by stem cell protein piwil2. Cancer research 98 20460541
2015 MIWI2 and MILI Have Differential Effects on piRNA Biogenesis and DNA Methylation. Cell reports 83 26279574
2010 Piwil2 is expressed in various stages of breast cancers and has the potential to be used as a novel biomarker. International journal of clinical and experimental pathology 81 20490325
2012 Piwil2 suppresses p53 by inducing phosphorylation of signal transducer and activator of transcription 3 in tumor cells. PloS one 76 22303479
2006 Stem cell protein Piwil2 modulates expression of murine spermatogonial stem cell expressed genes. Molecular reproduction and development 75 16261612
2010 Identification of Piwil2-like (PL2L) proteins that promote tumorigenesis. PloS one 71 20975993
2010 Piwil2 expressed in various stages of cervical neoplasia is a potential complementary marker for p16. American journal of translational research 56 20407605
2011 Stem cell protein Piwil2 modulates chromatin modifications upon cisplatin treatment. Mutation research 54 21310163
2012 Piwil2 modulates the proliferation and metastasis of colon cancer via regulation of matrix metallopeptidase 9 transcriptional activity. Experimental biology and medicine (Maywood, N.J.) 53 23104504
2015 PIWIL2 promotes progression of non-small cell lung cancer by inducing CDK2 and Cyclin A expression. Journal of translational medicine 49 26373553
2017 Roles of MIWI, MILI and PLD6 in small RNA regulation in mouse growing oocytes. Nucleic acids research 48 28115634
2019 Mitochondrial membrane-based initial separation of MIWI and MILI functions during pachytene piRNA biogenesis. Nucleic acids research 46 30590800
2004 Myoblast determination in the somatic and visceral mesoderm depends on Notch signalling as well as on milliways(mili(Alk)) as receptor for Jeb signalling. Development (Cambridge, England) 45 14757637
2020 TEX15 associates with MILI and silences transposable elements in male germ cells. Genes & development 44 32381626
2014 PIWIL2 induces c-Myc expression by interacting with NME2 and regulates c-Myc-mediated tumor cell proliferation. Oncotarget 44 25193865
2011 Germline stem cell gene PIWIL2 mediates DNA repair through relaxation of chromatin. PloS one 44 22110608
2012 Clinicopathologic Implications of PIWIL2 Expression in Colorectal Cancer. Korean journal of pathology 43 23110023
2016 Piwil2 is reactivated by HPV oncoproteins and initiates cell reprogramming via epigenetic regulation during cervical cancer tumorigenesis. Oncotarget 42 27602489
2018 A piRNA utilizes HILI and HIWI2 mediated pathway to down-regulate ferritin heavy chain 1 mRNA in human somatic cells. Nucleic acids research 37 30102404
2010 Expression of the Argonaute protein PiwiL2 and piRNAs in adult mouse mesenchymal stem cells. Biochemical and biophysical research communications 36 20460113
2014 Array-based DNA methylation profiling in male infertility reveals allele-specific DNA methylation in PIWIL1 and PIWIL2. Fertility and sterility 31 24524831
2012 HILI inhibits TGF-β signaling by interacting with Hsp90 and promoting TβR degradation. PloS one 31 22848678
2014 Piwil2 inhibits keratin 8 degradation through promoting p38-induced phosphorylation to resist Fas-mediated apoptosis. Molecular and cellular biology 30 25113562
2013 Expression analysis of four testis-specific genes AURKC, OIP5, PIWIL2 and TAF7L in acute myeloid leukemia: a gender-dependent expression pattern. Medical oncology (Northwood, London, England) 29 23292864
2015 Piwil2 modulates the invasion and metastasis of prostate cancer by regulating the expression of matrix metalloproteinase-9 and epithelial-mesenchymal transitions. Oncology letters 27 26622742
2020 Exosomes derived from Piwil2‑induced cancer stem cells transform fibroblasts into cancer‑associated fibroblasts. Oncology reports 24 32323829
2015 Correlation of HIWI and HILI Expression with Cancer Stem Cell Markers in Colorectal Cancer. Anticancer research 24 26026091
2021 PIWIL2 interacting with IKK to regulate autophagy and apoptosis in esophageal squamous cell carcinoma. Cell death and differentiation 21 33469229
2019 Isorhamnetin glycoside isolated from Opuntia ficus-indica (L.) MilI induces apoptosis in human colon cancer cells through mitochondrial damage. Chemico-biological interactions 21 31276661
2018 Aberrant Expression of PIWIL1 and PIWIL2 and Their Clinical Significance in Ductal Breast Carcinoma. Anticancer research 21 29599319
2022 Piwil2 (Mili) sustains neurogenesis and prevents cellular senescence in the postnatal hippocampus. EMBO reports 20 36472244
2017 Hili Inhibits HIV Replication in Activated T Cells. Journal of virology 20 28331090
2013 A novel in vitro model for cancer stem cell culture using ectopically expressed piwil2 stable cell line. Cell journal 20 24027667
2017 A MILI-independent piRNA biogenesis pathway empowers partial germline reprogramming. Nature structural & molecular biology 19 28530707
2012 The expression of the PIWI family members miwi and mili in mice testis is negatively affected by estrogen. Cell and tissue research 19 22628161
2018 PIWIL2 suppresses Siah2-mediated degradation of HDAC3 and facilitates CK2α-mediated HDAC3 phosphorylation. Cell death & disease 18 29555935
2014 Cloning, expression and methylation analysis of piwil2 in half-smooth tongue sole (Cynoglossus semilaevis). Marine genomics 18 24794875
2017 Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating the stability and activity of BMAL1 and CLOCK. Oncotarget 17 28903391
2014 A TALEN-based specific transcript knock-down of PIWIL2 suppresses cell growth in HepG2 tumor cell. Cell proliferation 17 25040173
2020 The role of Nrf2/PIWIL2/purine metabolism axis in controlling radiation-induced lung fibrosis. American journal of cancer research 16 33042615
2017 Piwil2-transfected human fibroblasts are cancer stem cell-like and genetically unstable. Oncotarget 16 28103575
2015 The clinical significances of the abnormal expressions of Piwil1 and Piwil2 in colonic adenoma and adenocarcinoma. OncoTargets and therapy 16 26064060
2020 CBP-mediated Wnt3a/β-catenin signaling promotes cervical oncogenesis initiated by Piwil2. Neoplasia (New York, N.Y.) 15 33190089
2019 Activation of pCREB/Nrf-2 signaling mediates re-positioning of liraglutide as hepato-protective for methotrexate -induced liver injury (MILI). Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 15 31362085
2017 HILI destabilizes microtubules by suppressing phosphorylation and Gigaxonin-mediated degradation of TBCB. Scientific reports 15 28393858
2009 Absence of PIWIL2 (HILI) expression in human bladder cancer cell lines and tissues. Cancer epidemiology 15 19683485
2022 Attenuation of Piwil2 induced by hypoxic postconditioning prevents cerebral ischemic injury by inhibiting CREB2 promoter methylation. Brain pathology (Zurich, Switzerland) 14 35794855
2023 PIWIL2 Regulates the Proliferation, Apoptosis and Colony Formation of Colorectal Cancer Cell Line. Iranian journal of biotechnology 12 36811102
2020 PIWIL-2 and piRNAs are regularly expressed in epithelia of the skin and their expression is related to differentiation. Archives of dermatological research 12 32166374
2020 Physiological impact and comparison of mutant screening methods in piwil2 KO founder Nile tilapia produced by CRISPR/Cas9 system. Scientific reports 11 32724054
2017 Identification and expression of piwil2 in turbot Scophthalmus maximus, with implications of the involvement in embryonic and gonadal development. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 11 28438683
2015 Sodium orthovanadate induces the apoptosis of SH-SY5Y cells by inhibiting PIWIL2. Molecular medicine reports 11 26647781
2015 HPV 16 infection up-regulates Piwil2, which affects cell proliferation and invasion in cervical cancer by regulating MMP-9 via the MAPK pathway. European journal of gynaecological oncology 11 26775345
2024 Dexmedetomidine promotes colorectal cancer progression via Piwil2 signaling. Cellular oncology (Dordrecht, Netherlands) 10 38592610
2022 A homozygous PIWIL2 frameshift variant affects the formation and maintenance of human-induced pluripotent stem cell-derived spermatogonial stem cells and causes Sertoli cell-only syndrome. Stem cell research & therapy 10 36153567
2024 PIWIL2/PDK1 Axis Promotes the Progression of Cervical Epithelial Lesions via Metabolic Reprogramming to Maintain Tumor-Initiating Cell Stemness. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 9 39499767
2018 Molecular characterization and expression of Piwil1 and Piwil2 during gonadal development and treatment with HCG and LHRH-A2 in Odontobutis potamophila. Gene 9 29331479
2015 Expression and clinical significance of PIWIL2 in hilar cholangiocarcinoma tissues and cell lines. Genetics and molecular research : GMR 9 26125915
2024 PiRNA-4447944 promotes castration-resistant growth and metastasis of prostate cancer by inhibiting NEFH expression through forming the piRNA-4447944-PIWIL2-NEFH complex. International journal of biological sciences 8 38993562
2022 Novel piRNA MW557525 regulates the growth of Piwil2-iCSCs and maintains their stem cell pluripotency. Molecular biology reports 8 35411481
2019 PIWIL2 stabilizes β-catenin to promote cell cycle and proliferation in tumor cells. Biochemical and biophysical research communications 8 31262447
2016 Decreased Expression of Bioinformatically Predicted piwil2-targetting microRNAs, miR-1267 and miR-2276 in Breast Cancer. Archives of Iranian medicine 8 27293058
2022 Multiple transcriptome analysis of Piwil2-induced cancer stem cells, including piRNAs, mRNAs and miRNAs reveals the mechanism of tumorigenesis and development. Molecular biology reports 7 35182325
2021 SCF Improves In Vitro Differentiation of SSCs Through Transcriptionally Up-regulating PRTM1, STRA8, c-KIT, PIWIL2, and OCT4 Genes. Reproductive sciences (Thousand Oaks, Calif.) 7 33492648
2018 Differential expression of PIWIL2 in papillary thyroid cancers. Gene 7 29369786
2024 DNA Methylation Mediates Sperm Quality via piwil1 and piwil2 Regulation in Japanese Flounder (Paralichthys olivaceus). International journal of molecular sciences 6 38892123
2017 An unusual intragenic promoter of PIWIL2 contributes to aberrant activation of oncogenic PL2L60. Oncotarget 6 28545024
2011 [Expression of Piwil2 and its relationship with tumor invasion and metastasis in papillary thyroid carcinoma]. Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery 6 21575418
2023 Stem Cell Protein PIWIL2 Promotes EMT Process and Stem Cell-Like Properties in MCF7 Breast Cancer Cell Line. Advanced biomedical research 5 38192888
2015 MILI, a PIWI family protein, inhibits melanoma cell migration through methylation of LINE1. Biochemical and biophysical research communications 5 25582775
2020 Generation of an iPSC line (HUSTi002-A) from fibroblasts of a patient with Sertoli cell-only syndrome carrying c.731_732delAT in PIWIL2 gene. Stem cell research 4 32006804
2021 Structural basis for RNA 3'-end recognition by the PIWIL2 PAZ domain. Biochemical and biophysical research communications 3 33774220
2016 Intragenic Locus in Human PIWIL2 Gene Shares Promoter and Enhancer Functions. PloS one 3 27248499
2020 PIWIL2 is overexpressed in adenomyotic lesions of women with diffuse adenomyosis. Archives of gynecology and obstetrics 2 32613450
2025 PIWIL2 downregulation in colon cancer promotes transposon activity and pro-tumorigenic phenotypes. Biology open 1 40789164
2025 GASZ directly recruits MILI to the intermitochondrial cement for piRNA biogenesis and male germ cell development. Nucleic acids research 1 41063345
2025 Cardiac Myofibroblast-Derived Small Extracellular Vesicles Moderate Fibrotic Responses via piRNA-62788/PIWIL2-Mediated SRF Silencing. Journal of extracellular vesicles 1 41311252
2023 The SW480 cell line, overexpressing PIWIL2 gene, maintains the expression of stemness and proliferation genes in the mice xenografts. Gastroenterology and hepatology from bed to bench 1 37070109
2023 PIWIL2 restrains the progression of thyroid cancer via interaction with miR-146a-3p. BMC endocrine disorders 1 37641092
2022 HiLi-chip: A high-throughput library construction chip for comprehensive profiling of environmental microbial communities. Environmental research 1 35690091
2015 [Histological features of tumor-bearing tissues formed by human fibroblasts after reprograming by Piwil2]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 1 26714595
2025 PIWIL2 downregulation in colon cancer promotes transposon activity and pro-tumorigenic phenotypes. bioRxiv : the preprint server for biology 0 40475606
2025 The effect of dendrosomal nanocurcumin on Wnt/β-catenin signaling pathway via PIWIL2 in MCF-7 breast cancer cells. Medical oncology (Northwood, London, England) 0 40719975
2025 Peptide‑based therapeutics targeting the SLC39A14‑PIWIL2 fusion in hepatocellular carcinoma. Genomics & informatics 0 41422314
2024 HEPPAR1 and PIWIL2 as Panel Markers for Hepatocellular Carcinoma. Asian Pacific journal of cancer prevention : APJCP 0 38918675
2024 Erratum: Stem Cell Protein PIWIL2 Promotes EMT Process and Stem Cell-Like Properties in MCF7 Breast Cancer Cell Line. Advanced biomedical research 0 39717251

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