Affinage

PIWIL2

Piwi-like protein 2 · UniProt Q8TC59

Length
973 aa
Mass
109.8 kDa
Annotated
2026-04-28
98 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIWIL2 (MILI/HILI) is a PIWI-clade Argonaute protein that functions as a piRNA-guided endonuclease essential for transposable element silencing, de novo DNA methylation, and germ cell development. Its DDH catalytic triad drives the ping-pong amplification cycle that generates secondary piRNAs from transposon transcripts, with its slicer activity selectively required for LINE-1 silencing; MILI is recruited to the intermitochondrial cement by GASZ and partners with TDRD1 (via symmetrically dimethylated arginines) and TEX15 to couple piRNA biogenesis to DNA methylation of retrotransposon loci in fetal and postnatal male germ cells (PMID:22020280, PMID:17446352, PMID:41063345, PMID:32381626). Beyond transposon defense, PIWIL2 forms an RNA-independent complex with translation initiation factors eIF3a/eIF4E/eIF4G to promote protein synthesis in germline stem cells, and conditional loss in adult hippocampal neural progenitors impairs neurogenesis and induces senescence (PMID:19114715, PMID:36472244). In somatic and tumor contexts, PIWIL2 engages STAT3/c-Src, NF-κB/IKK, and SRC–PI3K–AKT–GSK3β signaling axes to suppress apoptosis, stabilize β-catenin, and modulate circadian and TGF-β pathways (PMID:22303479, PMID:33469229, PMID:28903391, PMID:22848678). A homozygous loss-of-function frameshift in PIWIL2 causes Sertoli cell-only syndrome in humans, consistent with its indispensable role in spermatogonial stem cell maintenance (PMID:36153567).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2004 High

    Establishing that PIWIL2 is indispensable for male meiosis resolved whether mammalian PIWI proteins have non-redundant germline functions: Mili-knockout mice arrest at zygotene-to-early-pachytene, and MILI physically associates with the RNA helicase MVH.

    Evidence Targeted gene knockout in mice with co-immunoprecipitation of MILI–MVH

    PMID:14736746

    Open questions at the time
    • Molecular cargo of MILI unknown at this stage
    • Mechanism of meiotic arrest not defined
    • Whether MILI has catalytic activity was untested
  2. 2006 High

    Identification of MILI-bound piRNAs as a distinct class of 26–31 nt small RNAs with 5′-U bias revealed the molecular partner that defines PIWI protein function, transforming MILI from an orphan Argonaute into a piRNA effector.

    Evidence Small RNA cloning and sequencing from MILI immunoprecipitates, mouse testes

    PMID:16751777

    Open questions at the time
    • How piRNAs are generated was unknown
    • Whether MILI cleaves target RNA was untested
    • Functional consequence of piRNA binding not yet linked to transposon silencing
  3. 2007 High

    Demonstrating that MILI participates in a ping-pong piRNA amplification cycle and that its loss derepresses LINE-1/IAP elements with concomitant loss of L1 DNA methylation established the transposon-silencing function of the MILI–piRNA pathway.

    Evidence Deep sequencing of small RNAs from Mili-mutant mice; bisulfite methylation analysis

    PMID:17446352

    Open questions at the time
    • Whether MILI's own slicer activity drives ping-pong was not directly tested
    • Relative contributions of MILI versus MIWI2 to DNA methylation unresolved
  4. 2008 High

    Showing that both MILI and MIWI2 are required for de novo DNA methylation of retrotransposon regulatory regions in fetal germ cells placed MILI upstream of the epigenetic silencing machinery and distinguished its role from maintenance methylation.

    Evidence Bisulfite sequencing of TE regulatory regions in MILI-null and MIWI2-null fetal germ cells

    PMID:18381894

    Open questions at the time
    • Nuclear effector mediating MILI-directed methylation unknown
    • Whether MILI acts cell-autonomously versus through MIWI2 loading was unclear
  5. 2008 High

    Discovery that MILI forms an RNA-independent complex with eIF3a/eIF4E/eIF4G and positively regulates translation in germline stem cells revealed a piRNA-independent function in stem cell self-renewal.

    Evidence Reciprocal co-immunoprecipitation; translation rate measurement in mili-mutant seminiferous tubules

    PMID:19114715

    Open questions at the time
    • mRNAs translationally regulated by MILI not identified
    • Whether translation regulation is separable from piRNA function in vivo unknown
  6. 2009 High

    Mapping the MILI–TDRD1 interaction to symmetrically dimethylated arginines on MILI's N-terminus recognized by TDRD1's Tudor domains defined a post-translational code that organizes the piRNP complex and gates piRNA substrate selection.

    Evidence Affinity purification/mass spectrometry of MILI complexes; Co-IP with domain mapping; Tdrd1-null piRNA profiling

    PMID:19345100 PMID:19465913

    Open questions at the time
    • Enzymes catalyzing symmetric arginine dimethylation on MILI not identified
    • Whether TDRD1 loss affects DNA methylation directly was not tested
  7. 2011 High

    Knock-in of a catalytic-dead DDH→DAH mutation proved that MILI's intrinsic endonuclease activity is the engine of ping-pong piRNA amplification and is required for LINE-1 silencing and MIWI2 piRNA loading, while MIWI2 slicer activity is dispensable.

    Evidence Point-mutation knock-in mice (Mili-DAH); piRNA deep sequencing from homozygous mutant gonadocytes

    PMID:22020280

    Open questions at the time
    • Whether endonuclease activity contributes to IAP silencing specifically was debated
    • Structural basis of MILI slicer activity not resolved
  8. 2011 Medium

    Finding that Mili-KO MEFs are defective in repair of UV, cisplatin, and IR damage, with reduced H3 acetylation and chromatin relaxation, extended MILI's role beyond germ cells to a general chromatin-based facilitator of DNA damage repair.

    Evidence Mili-KO MEFs; CPD, Pt-GG, and DSB repair assays; histone acetylation measurement

    PMID:22110608

    Open questions at the time
    • Whether repair function depends on piRNAs or slicer activity unknown
    • Mechanism linking MILI to p300-mediated acetylation not defined
    • Not independently replicated
  9. 2012 High

    HITS-CLIP of MILI in postnatal testis defined the genome-wide piRNA precursor landscape, establishing that pachytene piRNAs are processed from Piwi-bound long precursor transcripts by distinct nucleolytic activities.

    Evidence HITS-CLIP of MILI and MIWI from postnatal mouse testes; RNA-seq

    PMID:22842725

    Open questions at the time
    • Identity of the 3′ trimming nuclease unknown at this point
    • How precursor transcription is regulated was unresolved
  10. 2012 Medium

    Identification of PIWIL2–STAT3–c-Src and PIWIL2–Hsp90–TβR complexes, along with earlier STAT3/Bcl-XL results, collectively outlined somatic oncogenic signaling roles: PIWIL2 represses p53 via STAT3 nuclear translocation and suppresses TGF-β signaling by promoting receptor degradation.

    Evidence Co-immunoprecipitation with domain mapping; luciferase reporters; ubiquitination assays in HEK-293 and NIH-3T3 cells

    PMID:16377660 PMID:22303479 PMID:22848678

    Open questions at the time
    • All somatic signaling studies from a single research group
    • Physiological relevance in normal somatic tissues not established
    • Whether piRNAs participate in these somatic functions untested
  11. 2015 High

    Refined catalytic-dead analysis showed MILI endonuclease activity is selectively required for LINE-1 but not IAP silencing, dissociating the two major transposon families as mechanistically distinct PIWI pathway targets.

    Evidence Mili(DAH) and Miwi2(DAH) knock-in mice; piRNA sequencing from fetal gonadocytes

    PMID:26279574

    Open questions at the time
    • Mechanism of slicer-independent IAP silencing by MILI not defined
    • Whether post-translational silencing contributes to IAP control unknown
  12. 2017 High

    Demonstration that GASZ directly recruits MILI to the intermitochondrial cement established the spatial organization principle for piRNA biogenesis: mitochondrial surface scaffolding separates MILI and MIWI entry into the pathway (MIWI recruited by TDRKH).

    Evidence Co-IP; genetic disruption of GASZ–MILI interaction in mice; piRNA-seq

    PMID:30590800 PMID:41063345

    Open questions at the time
    • Whether other IMC scaffolds exist for MILI is unknown
    • Structural basis of the GASZ–MILI interface unresolved
  13. 2017 High

    A MILI-independent piRNA biogenesis pathway was discovered that partially sustains MIWI2 function, overturning the model that MILI is absolutely required for all MIWI2 piRNA loading.

    Evidence piRNA deep sequencing of MIWI2 complexes in Mili-null fetal germ cells

    PMID:28530707

    Open questions at the time
    • Source of MILI-independent piRNAs not identified
    • Functional sufficiency of this pathway for transposon silencing unclear
  14. 2017 Medium

    Multiple studies expanded somatic PIWIL2 activities: binding rare tRNAs to inhibit HIV replication, destabilizing microtubules via TBCB, and suppressing circadian rhythms via SRC–PI3K–AKT–GSK3β-mediated stabilization of BMAL1/CLOCK.

    Evidence tRNA-seq and HIV assays in CD4+ T cells; Co-IP/microtubule polymerization assays; ChIP and circadian reporters

    PMID:28331090 PMID:28393858 PMID:28903391

    Open questions at the time
    • Each finding from a single lab without independent replication
    • Whether these somatic functions are piRNA-dependent is unclear
    • Physiological expression levels in somatic tissues not verified in most cases
  15. 2020 High

    TEX15 was identified as the nuclear effector linking MILI-directed piRNA signals to DNA methylation of transposable elements: Tex15-null mice phenocopy Mili methylation defects but retain piRNA production, placing TEX15 downstream of piRNA biogenesis.

    Evidence Co-IP of TEX15 with MILI from testis; Tex15-null mice; bisulfite sequencing and piRNA sequencing

    PMID:32381626

    Open questions at the time
    • How TEX15 communicates piRNA targeting information to the DNA methylation machinery unknown
    • Whether TEX15 acts in a complex with DNMT3 family members untested
  16. 2021 High

    Structural determination of the human PIWIL2 PAZ domain confirmed canonical RNA 3′-end recognition via a hydrophobic pocket accommodating 2-nt overhangs, providing the first atomic-resolution view of human PIWIL2.

    Evidence X-ray crystallography of PIWIL2 PAZ domain

    PMID:33774220

    Open questions at the time
    • Full-length PIWIL2 structure not determined
    • piRNA-bound PIWIL2 structure lacking
    • PIWI domain catalytic mechanism not structurally resolved
  17. 2022 Medium

    A human homozygous PIWIL2 loss-of-function variant was linked to Sertoli cell-only syndrome, and iPSC-derived models showed impaired spermatogonial stem cell maintenance with Wnt pathway inactivation, providing the first direct human genetic evidence for PIWIL2 in male infertility.

    Evidence Whole-exome sequencing of infertile patient; hiPSC differentiation; RNA-seq; Wnt pathway analysis

    PMID:36153567

    Open questions at the time
    • Single family reported
    • Whether Wnt inactivation is a direct or secondary consequence of PIWIL2 loss unknown
    • No rescue with wild-type PIWIL2 in the patient-derived model
  18. 2022 Medium

    Conditional Mili knockout in adult hippocampal neural progenitors demonstrated a non-germline role: MILI loss impairs neuronal differentiation, induces senescence, and derepresses piRNA-targeted repetitive elements, extending the piRNA pathway to postnatal brain function.

    Evidence Conditional Mili KO in adult mouse hippocampus; RNA-seq of neural progenitors

    PMID:36472244

    Open questions at the time
    • Whether piRNA-mediated TE silencing is the causal mechanism for neurogenesis failure not proven
    • Single lab with no independent replication
    • Behavioral consequences not assessed
  19. 2025 Medium

    PIWIL2-piRNA complexes were shown to function in post-transcriptional mRNA silencing outside the germline: piRNA-62788/PIWIL2 silences SRF to attenuate cardiac fibrosis, and PIWIL2 depletion in colon epithelium derepresses LINE-1 and promotes transformation, suggesting context-dependent tumor-suppressive versus oncogenic roles.

    Evidence Co-IP of piRNA-PIWIL2 complex with 3′ UTR reporter; PIWIL2 KD in Caco2 with piRNA-seq and LINE-1 assays; mouse cardiac model

    PMID:40789164 PMID:41311252

    Open questions at the time
    • Endogenous PIWIL2 expression levels in these somatic tissues not comprehensively validated
    • Direct target spectrum of somatic piRNA–PIWIL2 complexes remains narrow
    • Whether somatic PIWIL2 functions require slicer activity is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full-length structure of PIWIL2 in complex with piRNA, the complete catalog of its somatic piRNA targets, and the mechanistic basis for context-dependent tumor-suppressive versus oncogenic activity remain unresolved.
  • No full-length PIWIL2 or PIWIL2–piRNA co-structure
  • Somatic piRNA target repertoire largely uncharacterized
  • Mechanism distinguishing tumor-suppressive TE silencing from oncogenic signaling unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0098772 molecular function regulator activity 4 GO:0140098 catalytic activity, acting on RNA 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 3 GO:0005739 mitochondrion 2
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-162582 Signal Transduction 4 R-HSA-4839726 Chromatin organization 3 R-HSA-1266738 Developmental Biology 2 R-HSA-392499 Metabolism of proteins 1 R-HSA-73894 DNA Repair 1
Partners
GASZHDAC3HSP90MVHNME2STAT3TDRD1TEX15
Complex memberships
MILI–TDRD1 piRNP complexMILI–eIF3a/eIF4E/eIF4G translation complexPIWIL2–STAT3–c-Src signaling complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 MILI (PIWIL2) is essential for spermatogenesis; knockout mice are blocked at early prophase of first meiosis (zygotene to early pachytene). MILI physically binds MVH, an essential factor during the early spermatocyte stage, suggesting a functional association in post-transcriptional regulation. Targeted gene knockout in mice; co-immunoprecipitation of MILI and MVH Development (Cambridge, England) High 14736746
2006 MILI (PIWIL2) binds a novel class of 26-31 nt small RNAs (piRNAs) in mouse male germ cells; piRNAs accumulate at the onset of meiosis, show strong 5' uridine preference, and are processed from a limited number of genomic clusters. Small RNA cloning and sequencing from MILI immunoprecipitates from mouse testes Nature High 16751777
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 L1 elements, demonstrating a role in transposon suppression. Deep sequencing of small RNAs from Mili mutant mice; DNA methylation analysis; genetic epistasis 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 reduces piRNA expression and impairs de novo methylation. Bisulfite sequencing of retrotransposon regulatory regions in MILI-null and MIWI2-null fetal germ cells; piRNA expression analysis Genes & development High 18381894
2008 MILI (PIWIL2) is expressed in the cytoplasm of testicular germ line stem cells and is essential for self-renewing division; MILI forms a stable, RNA-independent complex with translation initiation factor eIF3a and associates with the eIF4E/eIF4G cap-binding complex, positively regulating protein synthesis. Co-immunoprecipitation of MILI with eIF3a, eIF4E, eIF4G; protein synthesis rate measurement in mili-mutant seminiferous tubules The Journal of biological chemistry High 19114715
2009 MILI (PIWIL2) specifically interacts with Tudor domain-containing protein 1 (TDRD1) via an RNA-independent interaction mediated through the N-terminal domain of MILI and the MYND domain/first two Tudor domains of TDRD1; this interaction does not contribute to piRNA biogenesis but is required for spermatogenesis. MILI also positively regulates Tdrd1 mRNA expression. Co-immunoprecipitation; domain-mapping with truncation mutants; genetic analysis of Mili and Tdrd1 mutant mice Current biology : CB High 19345100
2009 TDRD1 is specifically associated with the MILI piRNP complex throughout spermatogenesis; complex formation is promoted by recognition of symmetrically dimethylated arginines at the N-terminus of MILI by the Tudor domains of TDRD1. Loss of TDRD1 delocalizes MIWI2 from nucleus to cytoplasm and alters the MILI piRNA profile, allowing abundant cellular transcripts to enter the piRNA pathway. Affinity purification of MILI complexes from adult mouse testes followed by mass spectrometry; Co-IP; localization studies in Tdrd1-null mice Nature structural & molecular biology High 19465913
2011 The endonuclease activity of MILI (PIWIL2), dependent on the DDH catalytic triad, is required for transposon piRNA amplification (ping-pong cycle) and LINE-1 silencing. Knock-in of a catalytic-dead D→A mutation (Mili-DAH) abolishes transposon piRNA amplification and reduces MIWI2-bound piRNAs, causing spermatogenic failure; MIWI2 endonuclease activity is dispensable. Point mutation knock-in (D→A in DDH triad) in mice; piRNA deep sequencing from homozygous mutant gonadocytes; genetic rescue analysis Nature High 22020280
2005 PIWIL2 overexpression in NIH-3T3 cells activates Bcl-XL expression through upregulation of STAT3; siRNA silencing of PIWIL2 suppresses STAT3 and Bcl-XL and induces apoptosis. PIWIL2 overexpression inhibits apoptosis and promotes proliferation and cellular transformation (soft agar assay). Cancer gene array comparing PIWIL2-expressing vs control cells; siRNA knockdown; soft agar transformation assay Human molecular genetics Medium 16377660
2012 MILI (PIWIL2) and MIWI (PIWIL1) bind piRNA precursor transcripts in vivo; HITS-CLIP defined genome-wide target RNA repertoire and revealed that pachytene piRNAs are end products of RNA processing by distinct nucleolytic activities acting on Piwi-bound precursors. HITS-CLIP (high-throughput sequencing after crosslinking and immunoprecipitation) of MILI and MIWI from mouse postnatal testis; RNA-seq Nature structural & molecular biology High 22842725
2012 PIWIL2 directly associates with STAT3 via its PAZ domain and forms a PIWIL2/STAT3/c-Src triple protein complex; STAT3 is phosphorylated by c-Src and translocates to the nucleus to bind the p53 promoter and repress p53 transcription. Co-immunoprecipitation; domain-mapping (PAZ domain); immunofluorescence for STAT3 nuclear translocation; luciferase reporter for p53 promoter PloS one Medium 22303479
2012 HILI (human PIWIL2) suppresses TGF-β signaling by physically associating with Hsp90; HILI prevents formation of Hsp90-TβR heteromeric complexes, leading to increased Smurf2-mediated ubiquitination and degradation of TGF-β receptors (TβRI and TβRII), and abolishes Smad2/3 phosphorylation. Co-immunoprecipitation; ubiquitination assay; Western blot for Smad2/3 phosphorylation in HEK-293 cells PloS one Medium 22848678
2014 PIWIL2 promotes c-Myc transcription by interacting with NME2 (NM23) and facilitating NME2 binding to the G4-motif region within the c-Myc promoter; in a c-Myc-dependent manner, PIWIL2 upregulates RhoA and induces F-actin filament formation. Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); knockdown experiments measuring c-Myc and RhoA expression Oncotarget Medium 25193865
2014 PIWIL2 binds keratin 8 (K8) and p38 kinase through its PIWI domain, forming a PIWIL2/K8/p38 triple complex; PIWIL2 increases phosphorylation of K8 at Ser-73, inhibiting ubiquitin-mediated K8 degradation and thereby reducing Fas receptor membrane levels. PIWIL2 also represses p53 phosphorylation via p38, protecting cells from Fas-mediated apoptosis. Bacterial two-hybrid screening; co-immunoprecipitation; domain mapping (PIWI domain); phosphorylation assays; knockdown experiments Molecular and cellular biology Medium 25113562
2015 MILI (PIWIL2) endonuclease activity drives piRNA amplification selectively required for LINE-1 but not IAP silencing; MIWI2 endonuclease activity is dispensable for secondary piRNA biogenesis and transposon silencing, and hallmarks of piRNA amplification are observed in Miwi2-deficient gonadocytes. Analysis of Mili(DAH) and Miwi2(DAH) catalytic-dead knock-in mice; piRNA sequencing from fetal gonadocytes Cell reports High 26279574
2017 Mitochondria-anchored GASZ directly recruits MILI to the intermitochondrial cement (IMC) for piRNA biogenesis; loss of GASZ-MILI interaction reduces fetal piRNA levels, increases transposon expression, and impairs spermatogonial and spermatocyte development. Co-immunoprecipitation; genetic disruption of GASZ-MILI interaction in mice; piRNA sequencing; transposon expression analysis Nucleic acids research High 41063345
2017 HILI (human PIWIL2) inhibits HIV replication in activated CD4+ T cells by binding to select tRNA species including rare tRNAs; targeting rare tRNA(Arg(UCU)) with antisense oligonucleotides replicates HILI's inhibitory effect on HIV. HILI also inhibits IAP retrotransposition by a similar mechanism. HILI knockdown in activated T cells; tRNA-seq/binding assays; antisense oligonucleotide experiments; HIV replication assays Journal of virology Medium 28331090
2017 HILI (PIWIL2) destabilizes microtubules by interacting with TBCB; HILI inhibits Gigaxonin-mediated TBCB ubiquitination and degradation by promoting HSP90-TBCB binding while suppressing Gigaxonin-TBCB interaction, and also suppresses PAK1-induced TBCB phosphorylation. Co-immunoprecipitation; ubiquitination assay; microtubule polymerization assay; knockdown experiments Scientific reports Medium 28393858
2017 PIWIL2 suppresses circadian rhythms by activating the PI3K-AKT pathway through facilitating SRC-PI3K binding, thereby phosphorylating and inactivating GSK3β, which prevents GSK3β-induced phosphorylation and degradation of circadian proteins BMAL1 and CLOCK. PIWIL2 also directly binds E-Box sequences associated with the BMAL1/CLOCK complex to repress clock-controlled gene transcription. Co-immunoprecipitation; kinase activity assays; ChIP; circadian reporter assays; knockdown/overexpression experiments Oncotarget Medium 28903391
2017 A MILI-independent piRNA biogenesis pathway exists that sustains partial MIWI2 function and reprogramming activity in the absence of MILI; MIWI2's binding to piRNA and nuclear localization are partially independent of MILI. Genetic analysis of MILI-deficient mouse germ cells; deep sequencing of piRNAs from MIWI2 in Mili-null background Nature structural & molecular biology High 28530707
2018 PIWIL2 interacts with HDAC3, stabilizing it from Siah2-mediated ubiquitin-proteasomal degradation by competitive association with Siah2; PIWIL2 also facilitates CK2α-mediated phosphorylation of HDAC3 by promoting the HDAC3-CK2α interaction, thereby enhancing HDAC3 deacetylase activity. Co-immunoprecipitation; ubiquitination assay; HDAC3 activity assay; knockdown/overexpression experiments in cancer cells Cell death & disease Medium 29555935
2018 A human piRNA (piR-FTH1) negatively regulates ferritin heavy chain 1 (Fth1) mRNA at the post-transcriptional level in triple-negative breast cancer cells via a HIWI2 (PIWIL4)- and HILI (PIWIL2)-mediated mechanism. piRNA transfection; siRNA knockdown of HIWI2 and HILI; qRT-PCR and Western blot for Fth1 mRNA and protein levels Nucleic acids research Medium 30102404
2019 Mitochondria-anchored TDRKH specifically recruits MIWI to the intermitochondrial cement (IMC), but not MILI; TDRKH deficiency causes loss of MIWI from the chromatoid body and spermiogenic arrest, and also enables MILI-bound piRNA trimming, demonstrating a mitochondrial surface-based scaffolding mechanism that separates the initial entry of MIWI and MILI into the piRNA pathway. Co-immunoprecipitation; localization studies; piRNA sequencing from TDRKH-deficient mice; genetic analysis Nucleic acids research High 30590800
2019 PIWIL2 stabilizes β-catenin by suppressing GSK3β-induced phosphorylation and ubiquitination of β-catenin (via the SRC-PI3K-AKT pathway previously shown to inactivate GSK3β), leading to increased nuclear β-catenin accumulation and upregulation of CyclinD1 to promote cell cycle progression. Co-immunoprecipitation; phosphorylation and ubiquitination assays; nuclear fractionation; overexpression/knockdown experiments in tumor cells Biochemical and biophysical research communications Medium 31262447
2020 TEX15, a testis-specific protein, associates with MILI (PIWIL2) in testis; Tex15 mutant mice show TE DNA hypomethylation similar to Mili mutants but with intact piRNA production, suggesting TEX15 functions as a nuclear effector of MILI for TE silencing by DNA methylation. Co-immunoprecipitation of TEX15 with MILI from testis; genetic analysis of Tex15-null mice; bisulfite sequencing; piRNA sequencing Genes & development High 32381626
2021 PIWIL2 directly binds IKK and promotes its phosphorylation, leading to IκB phosphorylation and NF-κB nuclear translocation for apoptosis inhibition; simultaneously, PIWIL2 competitively inhibits IKK binding to TSC1, thereby deactivating mTORC1 and suppressing ULK1-mediated autophagy initiation. Co-immunoprecipitation; phosphorylation assays; competitive binding assays; mouse xenograft model with IKK-dependent rescue Cell death and differentiation Medium 33469229
2021 Crystal structure of the human PIWIL2 PAZ domain was solved; it adopts a canonical PAZ fold and uses a deep hydrophobic concave to accommodate 2 nt 3'-overhangs of RNA, a recognition mode conserved across human PIWIL proteins. X-ray crystallography of PIWIL2 PAZ domain; homology modeling of PIWIL2-RNA complex Biochemical and biophysical research communications High 33774220
2022 PIWIL2 (Mili) is essential for proper neurogenesis in the postnatal mouse hippocampus; depletion of Mili and piRNAs in adult hippocampal neural progenitor cells impairs differentiation toward neural fate, induces cellular senescence, and generates reactive glia. Transcripts modulated upon Mili depletion bear piRNA-complementary or homologous sequences, including repetitive elements and neurogenesis-related mRNAs. Conditional Mili KO in adult mouse hippocampus; RNA-seq of neural progenitor cells; immunofluorescence for senescence and differentiation markers EMBO reports Medium 36472244
2022 A homozygous loss-of-function frameshift variant in PIWIL2 (c.731_732delAT) causes Sertoli cell-only syndrome; using PIWIL2-/- hiPSC-derived germ cell models, formation and maintenance of spermatogonial stem cell-like cells was severely impaired, associated with inactivation of the Wnt signaling pathway. Whole-exome sequencing; in vitro hiPSC differentiation toward spermatogonial stem cells; RNA-seq; Wnt pathway inhibitor rescue experiments Stem cell research & therapy Medium 36153567
2011 PIWIL2 (Mili) mediates DNA repair through promotion of histone H3 acetylation and chromatin relaxation; Mili-knockout mouse embryonic fibroblasts exhibit defective repair of UV-induced CPDs, cisplatin Pt-GG adducts, and ionizing radiation-induced DSBs, and show increased apoptosis. PIWIL2 acts upstream of DDR pathways via the axis: PIWIL2→histone acetylation (via p300)→chromatin relaxation. Mili-KO MEF analysis; CPD repair assay after UV; Pt-GG repair assay after cisplatin; DSB repair after IR; histone acetylation and chromatin relaxation measurement PloS one Medium 22110608
2025 piRNA-62788 forms a functional complex with PIWIL2 that binds to the 3' UTR of Srf mRNA, leading to post-transcriptional silencing of serum response factor (SRF) and attenuation of cardiac fibrotic responses; this piRNA is packaged into small extracellular vesicles by AngII/AT2R signaling. Small RNA sequencing of sEVs; co-immunoprecipitation of piRNA-62788/PIWIL2 complex; 3' UTR luciferase reporter; overexpression/knockdown in cardiac fibroblasts; mouse transverse aortic constriction model Journal of extracellular vesicles Medium 41311252
2025 PIWIL2 depletion in colon epithelial Caco2 cells leads to loss of transposon-targeting non-canonical piRNAs, increased LINE-1 levels and activity, DNA damage, and increased anchorage-independent growth, indicating a tumor-suppressive role of PIWIL2 in colon epithelium via TE silencing. PIWIL2 knockdown in Caco2 cells; piRNA sequencing; LINE-1 activity reporter assay; γH2AX DNA damage assay; soft agar colony formation assay 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 1185 16751777
2007 Developmentally regulated piRNA clusters implicate MILI in transposon control. Science (New York, N.Y.) 804 17446352
2008 DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. Genes & development 722 18381894
2004 Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development (Cambridge, England) 622 14736746
2011 The endonuclease activity of Mili fuels piRNA amplification that silences LINE1 elements. Nature 281 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 112 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 82 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 74 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
2017 Roles of MIWI, MILI and PLD6 in small RNA regulation in mouse growing oocytes. Nucleic acids research 47 28115634
2015 PIWIL2 promotes progression of non-small cell lung cancer by inducing CDK2 and Cyclin A expression. Journal of translational medicine 47 26373553
2019 Mitochondrial membrane-based initial separation of MIWI and MILI functions during pachytene piRNA biogenesis. Nucleic acids research 45 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
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
2020 TEX15 associates with MILI and silences transposable elements in male germ cells. Genes & development 42 32381626
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
2015 Correlation of HIWI and HILI Expression with Cancer Stem Cell Markers in Colorectal Cancer. Anticancer research 24 26026091
2020 Exosomes derived from Piwil2‑induced cancer stem cells transform fibroblasts into cancer‑associated fibroblasts. Oncology reports 23 32323829
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
2021 PIWIL2 interacting with IKK to regulate autophagy and apoptosis in esophageal squamous cell carcinoma. Cell death and differentiation 20 33469229
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
2022 Piwil2 (Mili) sustains neurogenesis and prevents cellular senescence in the postnatal hippocampus. EMBO reports 19 36472244
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
2017 Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating the stability and activity of BMAL1 and CLOCK. Oncotarget 17 28903391
2014 Cloning, expression and methylation analysis of piwil2 in half-smooth tongue sole (Cynoglossus semilaevis). Marine genomics 17 24794875
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
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
2015 The clinical significances of the abnormal expressions of Piwil1 and Piwil2 in colonic adenoma and adenocarcinoma. OncoTargets and therapy 15 26064060
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) 13 35794855
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
2023 PIWIL2 Regulates the Proliferation, Apoptosis and Colony Formation of Colorectal Cancer Cell Line. Iranian journal of biotechnology 11 36811102
2020 Physiological impact and comparison of mutant screening methods in piwil2 KO founder Nile tilapia produced by CRISPR/Cas9 system. Scientific reports 11 32724054
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
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
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 10 28438683
2024 Dexmedetomidine promotes colorectal cancer progression via Piwil2 signaling. Cellular oncology (Dordrecht, Netherlands) 9 38592610
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 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) 8 39499767
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
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 7 38993562
2018 Differential expression of PIWIL2 in papillary thyroid cancers. Gene 7 29369786
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 6 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.) 6 33492648
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
2024 DNA Methylation Mediates Sperm Quality via piwil1 and piwil2 Regulation in Japanese Flounder (Paralichthys olivaceus). International journal of molecular sciences 5 38892123
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 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 PIWIL2 downregulation in colon cancer promotes transposon activity and pro-tumorigenic phenotypes. Biology open 0 40789164
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