Affinage

ZFP36L2

mRNA decay activator protein ZFP36L2 · UniProt P47974

Length
494 aa
Mass
51.1 kDa
Annotated
2026-06-11
63 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZFP36L2 is a CCCH tandem zinc finger (TZF) RNA-binding protein that recognizes AU-rich elements (AREs), specifically UAUUUAU heptamers, in the 3' UTRs of target mRNAs and triggers their decay, thereby acting as a master post-transcriptional regulator of cell-fate transitions and quiescence across reproduction, hematopoiesis, lymphocyte development, and innate immunity (PMID:14981510, PMID:15342461, PMID:35380695). The atomic basis of recognition is a pair of CCCH fingers that bind adjacent 5'-UAUU-3' subsites on single-stranded RNA, and target selection is further shaped by structural context, with high-affinity binding requiring presentation of the ARE in a flexible hairpin loop (PMID:14981510, PMID:28455422); multiple UAUUUAU motifs and an intact TZF domain are required for efficient destabilization (PMID:35380695, PMID:29426877). Once bound, ZFP36L2 recruits the CCR4-NOT deadenylase complex to promote deadenylation and degradation of target transcripts (PMID:25106868). This activity is reversibly controlled by ERK-downstream RSK, which phosphorylates the C-terminal region to dissociate CCR4-NOT and stabilize targets, and by cell-cycle-dependent ZYG11B-mediated polyubiquitination that eliminates the protein in interphase (PMID:25106868, PMID:29449217). Through these mechanisms ZFP36L2 enforces developmental checkpoints and quiescence: it clears maternal mRNAs and degrades histone-demethylase mRNAs to enable oocyte-to-embryo chromatin silencing and preimplantation development (PMID:15342461, PMID:29408237, PMID:34611029), maintains hematopoietic stem cell function and glucocorticoid-driven BFU-E self-renewal (PMID:19633199, PMID:23748442), and—redundantly with ZFP36L1—suppresses Notch1 and cell-cycle/DNA-damage regulons to control beta-selection and pre-BCR lymphocyte checkpoints (PMID:20622884, PMID:27102483, PMID:27566829). Additional context-dependent targets include Mdm2 mRNA, whose destabilization stabilizes P53 to suppress mTORC1 during cardiac pregnancy adaptation (PMID:35316214), as well as LDLR, LHR, Ikzf2/Helios, and Ifng (PMID:25106868, PMID:24830504, PMID:32655569, PMID:38980256). ZFP36L2 also functions in antiviral defense, binding viral RNA to drive XRN1-mediated flavivirus decay and binding HIV-1 Rev to block nuclear export of RRE-containing transcripts (PMID:39972499, PMID:41932956). Biallelic and TZF-domain ZFP36L2 variants that impair RNA binding or complex assembly cause recurrent preimplantation embryonic arrest and oocyte maturation defects in humans (PMID:34611029, PMID:39668715, PMID:39178021, PMID:38829516).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2004 High

    Established the atomic mechanism by which ZFP36L2 achieves sequence-specific ARE recognition, defining how a CCCH tandem zinc finger reads single-stranded AU-rich RNA.

    Evidence NMR structure of the TIS11d TZF domain bound to UUAUUUAUU RNA

    PMID:14981510

    Open questions at the time
    • Does not address recruitment of downstream decay machinery
    • Structure of full-length protein and its regulatory regions unresolved
  2. 2004 High

    Linked ARE-binding activity to physiological mRNA destabilization and demonstrated an essential in vivo role in early embryonic development.

    Evidence Cell transfection mRNA stability assay and Zfp36l2 knockout mice with two-cell embryo arrest

    PMID:15342461

    Open questions at the time
    • Specific maternal mRNA targets not identified at the time
    • Molecular basis of two-cell arrest left to later work
  3. 2009 High

    Extended the in vivo requirement for ZFP36L2 to definitive hematopoiesis, identifying it as a regulator of stem/progenitor maintenance.

    Evidence Competitive bone marrow reconstitution and fetal liver progenitor assays in knockout mice

    PMID:19633199

    Open questions at the time
    • Direct mRNA targets in HSCs not defined
    • Mechanism distinguishing maintenance vs differentiation unclear
  4. 2010 High

    Identified Notch1 mRNA as a direct ARE target and showed redundant ZFP36L1/L2 control of the thymocyte beta-selection checkpoint and tumor suppression.

    Evidence Conditional double-knockout mice, ARE binding assays, Notch1 expression analysis, T-ALL development

    PMID:20622884

    Open questions at the time
    • Quantitative contribution of each paralog not separated
    • Whether Notch1 is the sole relevant target unresolved
  5. 2013 High

    Placed ZFP36L2 downstream of glucocorticoid receptor signaling as a transcriptional target acting as a molecular switch for BFU-E self-renewal.

    Evidence GR ChIP on ZFP36L2 enhancers, knockdown and transplantation of BFU-E progenitors, mRNA binding analysis

    PMID:23748442

    Open questions at the time
    • Individual self-renewal target mRNAs not pinpointed
    • Connection to deadenylase recruitment not tested here
  6. 2014 High

    Defined the effector and regulatory mechanism: ZFP36L2 recruits the CCR4-NOT deadenylase, and RSK phosphorylation of its C-terminus reverses this to stabilize targets such as LDLR.

    Evidence Proteomic 3'UTR capture, CCR4-NOT co-IP, in vitro RSK phosphorylation, antisense disruption of LDLR-ZFP36L2 interaction

    PMID:25106868

    Open questions at the time
    • Specific phosphosites not all mapped
    • Generality of RSK control across all targets untested
  7. 2014 Medium

    Demonstrated direct destabilization of LHR mRNA via a defined ARE, linking ZFP36L2 loss to cAMP dysregulation, anovulation, and oocyte meiotic arrest.

    Evidence 3'UTR binding assay, ZFP36L2 overexpression, cAMP measurement, PKA inhibitor rescue in oocytes

    PMID:24830504

    Open questions at the time
    • Single lab without genetic loss-of-function in vivo
    • Deadenylase recruitment to LHR not directly shown
  8. 2016 High

    Showed ZFP36L1/L2 enforce B lymphocyte quiescence and the pre-BCR checkpoint by suppressing a coordinated post-transcriptional regulon driving S-phase entry.

    Evidence B-cell conditional double KO, cell cycle analysis, genome-wide target identification, VDJ recombination assays

    PMID:27102483

    Open questions at the time
    • Hierarchy among regulon targets not established
    • Paralog-specific roles not dissected
  9. 2016 High

    Established that the same paralog pair enforces beta-selection by limiting DNA damage and cell-cycle transcripts, preventing replication stress and chromosomal instability.

    Evidence Genome-wide target identification in primary thymocytes with conditional double KO and expression profiling

    PMID:27566829

    Open questions at the time
    • Causal target(s) for genomic instability not isolated
    • Mechanism connecting DDR transcript control to checkpoint timing incomplete
  10. 2017 Medium

    Refined the target recognition rule, showing RNA secondary structure—ARE presentation in a hairpin loop—is critical for high-affinity binding.

    Evidence SHAPE-MaP structural probing, gel-shift assays, and mutagenesis on LHR mRNA 3'UTR

    PMID:28455422

    Open questions at the time
    • Generality of structural requirement across other targets untested
    • In vivo relevance of hairpin context not assessed
  11. 2018 High

    Connected ZFP36L2 to oocyte-to-embryo chromatin silencing by showing it degrades histone-demethylase mRNAs to allow H3K4/H3K9 methylation and global transcriptional silencing.

    Evidence Oocyte-specific conditional KO, single-cell RNA-seq, RIP for bound mRNAs, histone methylation analysis

    PMID:29408237

    Open questions at the time
    • Direct demethylase targets vs secondary effects partly intertwined
    • Temporal coupling to maternal mRNA clearance not fully resolved
  12. 2018 Medium

    Revealed cell-cycle control of ZFP36L2 protein abundance via ZYG11B-mediated ubiquitination and a role in cisplatin-induced S-phase arrest.

    Evidence Cell cycle synchronization, polyubiquitination assay, cisplatin arrest analysis, knockdown

    PMID:29449217

    Open questions at the time
    • Degron recognized by ZYG11B not mapped
    • Single lab; physiological setting of cisplatin response untested in vivo
  13. 2018 Medium

    Demonstrated that RNA-binding-dependent suppression of cyclin D underlies ZFP36L2 antiproliferative, G1-arresting activity, independent of p53.

    Evidence Inducible overexpression and TZF domain mutagenesis in T-REx-293 cells with cyclin D measurement

    PMID:29426877

    Open questions at the time
    • Direct binding to cyclin D mRNA ARE not shown here
    • Overexpression-based; endogenous relevance limited
  14. 2020 Medium

    Identified Ikzf2 (Helios) mRNA as a direct ARE target whose destabilization tunes regulatory T cell function.

    Evidence RIP, forced ZFP36L2 expression in Tregs, RNA-seq, and iTreg suppression assays

    PMID:32655569

    Open questions at the time
    • Single lab with overexpression approach
    • In vivo Treg phenotype of endogenous loss not tested
  15. 2021 Low

    Reported association of ZFP36L2 with lncRNA PVT1 influencing mitochondrial dynamics in cardiomyocyte ischemia/reperfusion injury.

    Evidence RNA pulldown, FISH, luciferase reporter, in vivo I/R model, mitochondrial electron microscopy

    PMID:34131106

    Open questions at the time
    • Studied primarily as a lncRNA axis; direct ZFP36L2 RNA-decay mechanism not established
    • Single lab without reciprocal validation
  16. 2021 Medium

    Established human disease relevance by linking biallelic ZFP36L2 variants to failure of maternal mRNA decay and recurrent preimplantation embryo arrest.

    Evidence Whole exome sequencing, in vitro HeLa mRNA decay assay, single-cell RNA-seq of zygotes

    PMID:34611029

    Open questions at the time
    • Variant effect tested largely in HeLa rather than native oocytes/zygotes
    • Single family-level genetic evidence
  17. 2022 High

    Defined a ZFP36L2→Mdm2 mRNA decay→P53→SESN2/REDD1→mTORC1 axis governing cardiac adaptation to pregnancy, with rapamycin rescue.

    Evidence Cardiac-specific conditional KO, Mdm2 destabilization assay, P53/SESN2/REDD1 measurement, echocardiography, rapamycin treatment

    PMID:35316214

    Open questions at the time
    • Whether ZFP36L2 directly binds Mdm2 ARE via the same TZF mechanism shown elsewhere not detailed
    • Human peripartum cardiomyopathy link not established genetically
  18. 2022 Medium

    Quantified the binding rule, showing the 7-mer UAUUUAU motif and motif multiplicity dictate target destabilization, validated with the C176S zinc-finger mutant and a new target Elavl2.

    Evidence Conditional KO spleen RNA-seq, gel-shift assays on candidate targets, Elavl2 3'UTR reporter, C176S mutant overexpression

    PMID:35380695

    Open questions at the time
    • Genome-wide motif rules from a single tissue
    • Affinity contribution of structural context not integrated
  19. 2024 Medium

    Provided biochemical and structural explanation of how TZF-domain missense variants abolish RNA binding.

    Evidence Gel-shift assays of five nsSNP variants with molecular docking and dynamics simulations

    PMID:39668715

    Open questions at the time
    • Functional consequences in cells/organisms not tested
    • Variant frequency/disease association not established
  20. 2024 Medium

    Placed ZFP36L2 within the subcortical maternal complex and showed pathogenic variants disrupt mRNA stability and chromatin marks, causing embryonic arrest.

    Evidence Co-IP in 293T cells, oocyte microinjection of variant cRNAs, exome sequencing, histone methylation analysis

    PMID:39178021

    Open questions at the time
    • SCMC interaction shown by single Co-IP without reciprocal confirmation
    • Direct vs indirect SCMC membership unresolved
  21. 2024 Medium

    Identified compound heterozygous variants impairing a ZFP36L2-CONT6L complex and mRNA degradation, causing oocyte maturation defects.

    Evidence HeLa transfection, RT-PCR, single-cell RNA-seq of oocytes, Co-IP of ZFP36L2-CONT6L complex

    PMID:38829516

    Open questions at the time
    • Single Co-IP for novel complex partner without orthogonal validation
    • Mechanistic role of CONT6L association undefined
  22. 2024 Medium

    Showed temporally selective control of IFN-γ during prolonged T cell activation via ARE-dependent Ifng mRNA destabilization.

    Evidence T cell-specific conditional KO, Ifng mRNA stability assay, flow cytometry across time points, tumor-infiltrating T cell analysis

    PMID:38980256

    Open questions at the time
    • Mechanism of time-dependent selectivity not explained molecularly
    • Single lab
  23. 2025 High

    Established an antiviral role against HIV-1 through Rev binding and blockade of RRE-containing transcript nuclear export, downstream of IFN-β.

    Evidence Overexpression/knockdown, reciprocal Co-IP with Rev mutant validation, nuclear export assay, ex vivo CD4+ T cell reconstitution

    PMID:41932956

    Open questions at the time
    • Whether RNA-decay versus protein-protein mechanism predominates not fully separated
    • Structural basis of ZFP36L2-Rev interaction unknown
  24. 2025 Medium

    Defined a distinct antiviral mechanism against flaviviruses via direct viral RNA binding and XRN1-dependent decay within replication complexes, independent of processing bodies.

    Evidence Overexpression/knockdown, plaque assay, RIP for viral RNA, confocal colocalization with XRN1/NS3, replicon stability assay, P-body disruption

    PMID:39972499

    Open questions at the time
    • Direct interaction with XRN1 vs colocalization not distinguished
    • Single lab; in vivo antiviral relevance untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZFP36L2's shared molecular toolkit—ARE binding, CCR4-NOT recruitment, and post-translational regulation—is differentially deployed to select context-specific targets across tissues and to switch between mRNA decay and protein-blockade (e.g., HIV-1 Rev) modes remains unresolved.
  • No unified model for target selectivity across cell types
  • Determinants choosing decay vs nuclear-export-blockade not defined
  • Full-length structure and regulatory phosphosite map incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 8 GO:0140098 catalytic activity, acting on RNA 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 6 R-HSA-1474165 Reproduction 5 R-HSA-1640170 Cell Cycle 4 R-HSA-8953854 Metabolism of RNA 4
Partners
HIV-1 REVRPS6KA/RSKXRN1ZFP36L1ZYG11B
Complex memberships
CCR4-NOT deadenylase complexsubcortical maternal complex (SCMC)

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 The NMR structure of the TIS11d (ZFP36L2) tandem zinc finger (TZF) domain bound to 5'-UUAUUUAUU-3' RNA was solved, revealing a pair of novel CCCH fingers (CX8CX5CX3H type) separated by an 18-residue linker. The two zinc fingers bind symmetrically to adjacent 5'-UAUU-3' subsites on single-stranded RNA via electrostatic and hydrogen-bonding interactions, with intercalative stacking between conserved aromatic side chains and RNA bases. Sequence specificity is achieved by intermolecular hydrogen bonds between TIS11d main-chain functional groups and Watson-Crick edges of the bases. NMR structure determination with RNA-bound complex Nature structural & molecular biology High 14981510
2004 ZFP36L2 (Zfp36l2) decreases the stability of AU-rich element (ARE)-containing transcripts in cell transfection assays, functioning as an mRNA-binding and destabilizing protein. Knockout of Zfp36l2 in mice causes complete female infertility with embryo arrest at the two-cell stage, implicating ZFP36L2 in physiological control of early embryonic development through maternal mRNA turnover. Gene knockout in mice; embryo transfer experiments; cell transfection mRNA stability assay Development (Cambridge, England) High 15342461
2009 Complete Zfp36l2 knockout mice exhibit defective definitive hematopoiesis: fetal liver hematopoietic stem cells from KO mice are unable to reconstitute the hematopoietic system of lethally irradiated recipients, establishing ZFP36L2 as a critical modulator of hematopoietic stem and progenitor cell maintenance through mRNA stability control. Competitive bone marrow reconstitution; fetal liver hematopoietic progenitor colony assays; Zfp36l2 knockout mice Blood High 19633199
2010 ZFP36L1 and ZFP36L2 interact with evolutionarily conserved AU-rich elements in the 3' UTR of Notch1 mRNA and suppress its expression. Conditional double deletion of ZFP36L1 and ZFP36L2 during thymopoiesis leads to elevated Notch1 in untransformed thymocytes, accumulation of cells that bypass the beta-selection checkpoint without TCRbeta expression, and development of Notch1-dependent T-ALL. Conditional knockout mice; ARE binding assays; Notch1 mRNA/protein expression analysis in thymocytes Nature immunology High 20622884
2012 The ΔN-ZFP36L2 mutant (N-terminal 29 aa deleted) shuttles between cytoplasm and nucleus, binds to ARE-containing RNAs, and promotes deadenylation of a model ARE transcript in cell-based co-transfection assays, similar to wild-type ZFP36L2. However, ΔN-ZFP36L2 is substantially more resistant to LPS-induced down-regulation than the wild-type protein, suggesting that embryonic arrest is related to failure to appropriately down-regulate the protein upon stimulation. Subcellular fractionation; RNA-binding assay; co-transfection deadenylation assay; LPS stimulation in bone marrow-derived macrophages The Journal of biological chemistry Medium 22367205
2013 ZFP36L2 is a transcriptional target of the glucocorticoid receptor (GR) in burst-forming unit-erythroid (BFU-E) progenitors and is required for glucocorticoid-induced BFU-E self-renewal. ZFP36L2 preferentially binds to mRNAs induced during terminal erythroid differentiation and negatively regulates their expression, functioning as a molecular switch promoting BFU-E self-renewal. Knockdown of ZFP36L2 in cultured BFU-E cells; transplantation of erythroid progenitors; GR ChIP on ZFP36L2 enhancer regions; mRNA binding analysis Nature High 23748442
2014 ZFP36L1 and ZFP36L2 bind to the 3' UTR of LDLR mRNA and recruit the CCR4-NOT deadenylase complex, destabilizing the mRNA. The C-terminal regions of ZFP36L1 and ZFP36L2 are directly phosphorylated by p90 ribosomal S6 kinase (RSK), a kinase downstream of ERK, causing dissociation of the CCR4-NOT complex and stabilization of LDLR mRNA. Proteomic approach to identify 3'-UTR binding proteins; co-immunoprecipitation of CCR4-NOT complex; in vitro phosphorylation assay with RSK; antisense oligonucleotide disruption of LDLR mRNA/ZFP36L2 interaction Nucleic acids research High 25106868
2014 ZFP36L2 binds to the 3' UTR of luteinizing hormone receptor (LHR) mRNA at ARE2197 (UAUUUAU), and decreased expression of ZFP36L2 correlates with higher LHR mRNA levels. Overexpression of ZFP36L2 decreases endogenous LHR mRNA expression. Lack of ZFP36L2-mediated LHR mRNA downregulation is associated with elevated cAMP/adenylyl cyclase activity upon LH stimulation, anovulation, and oocyte meiotic arrest. 3'UTR binding assay; overexpression of ZFP36L2 in cell lines; cAMP measurement; PKA inhibitor rescue in oocytes PloS one Medium 24830504
2016 ZFP36L1 and ZFP36L2 are critical for maintaining B lymphocyte quiescence before pre-BCR expression and for reestablishing quiescence after pre-BCR-induced expansion. They suppress a posttranscriptional regulon of mRNAs whose protein products cooperatively promote S-phase entry, thereby promoting VDJ recombination and effective selection at the pre-BCR checkpoint. Conditional double knockout mice in B cell lineage; cell cycle analysis; genome-wide mRNA target identification; functional VDJ recombination assays Science (New York, N.Y.) High 27102483
2016 Zfp36l1 and Zfp36l2 act redundantly in thymocytes to enforce the beta-selection checkpoint by suppressing DNA damage response and cell cycle transcripts. Double-negative 3 thymocytes lacking Zfp36l1/l2 share a gene expression profile with post-selected DN3b cells despite absence of TCRbeta, and the proteins limit DNA damage responses to prevent chromosomal instability and replication stress. Genome-wide mRNA target identification in primary mouse thymocytes; conditional double knockout; gene expression profiling Journal of immunology High 27566829
2017 ZFP36L2 binds specifically to a functional ARE (UAUUUAU heptamer) in a hairpin loop structure within the LHR mRNA 3'UTR. The structural context—placement of the ARE in a hairpin loop with flexible stem—is critical for high-affinity ZFP36L2 binding; mutations enforcing strong base-pairing in the proximal stem drastically reduced binding affinity. The same structural constraint was conserved in human LHR mRNA. SHAPE-MaP (selective 2' hydroxyl acylation by primer extension-mutational profiling); gel-shift binding assays; site-directed mutagenesis of ARE-flanking sequences RNA (New York, N.Y.) Medium 28455422
2018 ZFP36L2 directly binds to and degrades histone demethylase mRNAs (targeting H3K4 and H3K9 demethylases) in oocytes, triggering widespread shifts in H3K4 and H3K9 methylation. Oocyte-specific loss of ZFP36L2 prevents global transcriptional silencing by failing to downregulate mRNAs encoding transcription and chromatin modification regulators; oocytes lacking Zfp36l2 fail to accumulate H3K4 and H3K9 methylation marks required for the transcriptionally silent, developmentally competent state. Oocyte-specific conditional knockout; single-cell RNA sequencing; RIP for ZFP36L2-bound mRNAs; histone methylation analysis; functional fertility assays Developmental cell High 29408237
2018 ZFP36L2 protein abundance is regulated post-translationally through the cell cycle: it is eliminated after release from M phase, and ZYG11B-based E3 ligase mediates its polyubiquitination in interphase. ZFP36L2 is required for cisplatin-induced S-phase arrest; its accumulation under DNA replication stress suppresses G1/S cyclins, and ZFP36L2 silencing impairs cell viability in the presence of cisplatin-induced DNA lesions. Cell cycle synchronization and protein abundance analysis; polyubiquitination assay; cisplatin-induced S-phase arrest analysis; ZFP36L2 knockdown Biology open Medium 29449217
2018 Overexpression of ZFP36L2 inhibits cell proliferation and arrests the cell cycle at G1 phase in a cyclin D-dependent and p53-independent manner. Mutation of the TZF domain of ZFP36L2 abolishes its antiproliferative activity and ability to suppress cyclin D expression, demonstrating that RNA-binding activity is required for growth suppression. Inducible overexpression in T-REx-293 cells; knockdown experiments; TZF domain mutagenesis; cell cycle analysis; cyclin D protein/mRNA measurement Scientific reports Medium 29426877
2020 ZFP36L2 directly binds to and destabilizes the 3' UTR of Ikzf2 (Helios) mRNA, which contains AU-rich elements, reducing Helios expression in Foxp3+ regulatory T cells and suppressing induced Treg function. RNA immunoprecipitation (ZFP36L2 binding to Ikzf2 3'UTR); forced ZFP36L2 expression in Tregs; RNA-sequence analysis of transcriptional targets; functional iTreg suppression assays Frontiers in immunology Medium 32655569
2021 Biallelic variants in ZFP36L2 (including p.Ser308_Ser310del) prevent maternal mRNA decay in zygotes and HeLa cells, causing recurrent preimplantation embryo developmental arrest. This establishes ZFP36L2-mediated maternal mRNA decay as required for human preimplantation embryo development. Whole exome sequencing; Sanger sequencing validation; in vitro functional assay of mRNA decay in HeLa cells; single-cell RNA sequencing of zygotes Journal of medical genetics Medium 34611029
2022 ZFP36L2 negatively regulates mTORC1 during pregnancy by destabilizing Mdm2 mRNA, leading to P53 stabilization, increased SESN2 and REDD1 expression, and consequent mTORC1 inhibition. Cardiac-specific Zfp36l2 deletion causes peripartum cardiomyopathy-like rapid cardiac dysfunction after delivery; prenatal rapamycin treatment of these mice improves postpartum cardiac function. Cardiac-specific conditional knockout mice; rapamycin treatment; Mdm2 mRNA destabilization assay; P53/SESN2/REDD1 protein level measurement; echocardiography The Journal of clinical investigation High 35316214
2022 ZFP36L2 requires a 7-mer UAUUUAU motif to bind target mRNAs, and targets with multiple such motifs are preferentially destabilized. Elavl2 mRNA (containing three 7-mer motifs) is a novel ZFP36L2 target in spleen; overexpression of ZFP36L2 but not a C176S mutant (zinc finger mutant) reduces Elavl2 mRNA, and this effect is dependent on the Elavl2 3'UTR and its 7-mer AREs. RNA-seq of conditional KO spleen; gel-shift mobility assays on 12 putative targets; reporter assay with Elavl2 3'UTR; ZFP36L2 C176S zinc finger mutant overexpression Nucleic acids research Medium 35380695
2024 Five nsSNP variants in the tandem zinc finger domain of ZFP36L2 (Y154H, R160W, R184C, G204D, C206F) dramatically reduce RNA binding compared to wild-type protein, as validated by gel shift assays. Structural modeling and molecular dynamics simulations provide atomic-level explanations for how these variants disrupt protein-RNA interactions. Gel shift assays; molecular docking; molecular dynamics simulations; structural modeling (DUET, DynaMut, PyMOL) RNA biology Medium 39668715
2024 ZFP36L2 is a component of the human subcortical maternal complex (SCMC), as demonstrated by co-immunoprecipitation in 293T cells. Pathogenic ZFP36L2 variants (p.Ala241Pro and p.Pro291dup) disrupt mRNA target stability and lead to aberrant H3K4me3 and H3K9me3 levels, causing embryonic development arrest. Co-immunoprecipitation in 293T cells; microinjection of ZFP36L2 cRNA variants into mouse oocytes; whole exome sequencing; histone methylation analysis Molecular human reproduction Medium 39178021
2024 Compound heterozygous ZFP36L2 variants (p.His62Gln and p.Pro290Leu) compromise the binding capacity of the ZFP36L2-CONT6L complex and impair mRNA degradation in HeLa cells and mouse oocytes, causing oocyte maturation defects. Transient transfection in HeLa cells; real-time RT-PCR; single-cell RNA sequencing of mouse and human oocytes; co-IP of ZFP36L2-CONT6L complex Journal of assisted reproduction and genetics Medium 38829516
2024 ZFP36L2 regulates IFN-γ production in a time-dependent manner: T cell-specific deletion has no effect on cytokine production at early time points (2–6 h) but specifically dampens IFN-γ production during prolonged T cell activation (20–48 h) by destabilizing Ifng mRNA in an AU-rich element-dependent manner. T cell-specific conditional KO (CD4-cre); mRNA stability assay for Ifng; flow cytometry for IFN-γ production at multiple time points; tumor-infiltrating T cell analysis European journal of immunology Medium 38980256
2025 ZFP36L2 acts as an IFN-β-induced innate inhibitor of HIV-1 replication by binding to the HIV-1 Rev protein and blocking nuclear export of Rev response element (RRE)-containing viral transcripts, thereby preventing downstream viral protein expression. A Rev mutant lacking amino acids 109–116 fails to bind ZFP36L2 and resists ZFP36L2-mediated inhibition. ZFP36L2 silencing impairs IFN-β-mediated HIV-1 inhibition; overexpression suppresses viral replication. ZFP36L2 overexpression/knockdown lentiviral system; co-IP of ZFP36L2-Rev interaction; Rev mutant analysis; nuclear export assay for RRE-containing transcripts; ex vivo CD4+ T cell reconstitution Nature communications High 41932956
2025 ZFP36L2 inhibits flavivirus (JEV and dengue virus) infection solely through the 5'-3' XRN1 RNA decay pathway. ZFP36L2 directly binds viral RNA via its CCCH-type zinc finger motifs and colocalizes with XRN1 and viral NS3 within replication complexes (RCs), facilitating XRN1-mediated degradation of viral RNA. Disruption of processing bodies does not affect ZFP36L2 antiviral activity. Lentiviral overexpression/knockdown; plaque assay; RNA immunoprecipitation; confocal microscopy colocalization; JEV replicon stability assay; processing body disruption experiment Journal of biomedical science Medium 39972499
2021 ZFP36L2 directly associates with lncRNA PVT1 in cardiomyocytes under hypoxia/reoxygenation injury, and this interaction alters mitochondrial fission and fusion. ZFP36L2 manipulation affects PVT1-miR-21-5p-MARCH5-mediated mitochondrial morphology during myocardial I/R injury. RNA pulldown; subcellular fractionation; FISH; luciferase reporter assay; in vivo I/R mouse model; transmission electron microscopy of mitochondria Cell death & disease Low 34131106
1995 ERF-2 (ZFP36L2) was cloned as the human homologue of the murine Tis11d gene. The encoded protein contains transactivation-like motifs, an unusual Cys-Ser-Ala-rich motif, and sequence similarity at the C-terminus with another Tis11 family member, ERF-1. The human protein has an additional 97 amino acids at its C-terminal end relative to the mouse homologue. cDNA cloning and sequencing; sequence alignment Gene Low 7835719

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Recognition of the mRNA AU-rich element by the zinc finger domain of TIS11d. Nature structural & molecular biology 302 14981510
2010 Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia. Nature immunology 177 20622884
1999 Erf2, a novel gene product that affects the localization and palmitoylation of Ras2 in Saccharomyces cerevisiae. Molecular and cellular biology 151 10490616
2016 RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence. Science (New York, N.Y.) 143 27102483
2004 The CCCH tandem zinc-finger protein Zfp36l2 is crucial for female fertility and early embryonic development. Development (Cambridge, England) 132 15342461
2010 Mutational analysis of Saccharomyces cerevisiae Erf2 reveals a two-step reaction mechanism for protein palmitoylation by DHHC enzymes. The Journal of biological chemistry 131 20851885
2009 Targeted disruption of Zfp36l2, encoding a CCCH tandem zinc finger RNA-binding protein, results in defective hematopoiesis. Blood 123 19633199
2013 ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors. Nature 93 23748442
2006 Sl-ERF2, a tomato ethylene response factor involved in ethylene response and seed germination. Plant & cell physiology 89 16857696
2018 Chromatin Modification and Global Transcriptional Silencing in the Oocyte Mediated by the mRNA Decay Activator ZFP36L2. Developmental cell 80 29408237
2014 ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway. Nucleic acids research 78 25106868
2018 ZFP36L1 and ZFP36L2 inhibit cell proliferation in a cyclin D-dependent and p53-independent manner. Scientific reports 63 29426877
2016 The RNA-Binding Proteins Zfp36l1 and Zfp36l2 Enforce the Thymic β-Selection Checkpoint by Limiting DNA Damage Response Signaling and Cell Cycle Progression. Journal of immunology (Baltimore, Md. : 1950) 59 27566829
2017 ZFP36L2 promotes cancer cell aggressiveness and is regulated by antitumor microRNA-375 in pancreatic ductal adenocarcinoma. Cancer science 51 27862697
2019 An ERF2-like transcription factor regulates production of the defense sesquiterpene capsidiol upon Alternaria alternata infection. Journal of experimental botany 47 31294452
2021 Genome-wide identification and functional analysis of the ERF2 gene family in response to disease resistance against Stemphylium lycopersici in tomato. BMC plant biology 42 33530947
2021 ZFP36L2 regulates myocardial ischemia/reperfusion injury and attenuates mitochondrial fusion and fission by LncRNA PVT1. Cell death & disease 40 34131106
2012 The Erf4 subunit of the yeast Ras palmitoyl acyltransferase is required for stability of the Acyl-Erf2 intermediate and palmitoyl transfer to a Ras2 substrate. The Journal of biological chemistry 40 22904317
2014 The RNA-binding protein, ZFP36L2, influences ovulation and oocyte maturation. PloS one 36 24830504
1995 ERF-2, the human homologue of the murine Tis11d early response gene. Gene 34 7835719
2009 Induced fit for mRNA/TIS11d complex. The Journal of chemical physics 31 19778152
2020 RNA-Binding Protein ZFP36L2 Downregulates Helios Expression and Suppresses the Function of Regulatory T Cells. Frontiers in immunology 30 32655569
2021 Biallelic variants in ZFP36L2 cause female infertility characterised by recurrent preimplantation embryo arrest. Journal of medical genetics 28 34611029
2015 Functional regulation of Zfp36l1 and Zfp36l2 in response to lipopolysaccharide in mouse RAW264.7 macrophages. Journal of inflammation (London, England) 28 26180518
2018 The RNA-binding proteins Zfp36l1 and Zfp36l2 act redundantly in myogenesis. Skeletal muscle 25 30526691
2021 CstF64-Induced Shortening of the BID 3'UTR Promotes Esophageal Squamous Cell Carcinoma Progression by Disrupting ceRNA Cross-talk with ZFP36L2. Cancer research 21 34607841
2012 Characterization of DeltaN-Zfp36l2 mutant associated with arrest of early embryonic development and female infertility. The Journal of biological chemistry 21 22367205
2006 TIS11D is a candidate pro-apoptotic p53 target gene. Cell cycle (Georgetown, Tex.) 21 17172869
2023 Downregulation of Linc00173 increases BCL2 mRNA stability via the miR-1275/PROCA1/ZFP36L2 axis and induces acquired cisplatin resistance of lung adenocarcinoma. Journal of experimental & clinical cancer research : CR 19 36627670
2022 Long noncoding RNA ZFP36L2-AS functions as a metabolic modulator to regulate muscle development. Cell death & disease 19 35449125
2018 ZFP36L2 is a cell cycle-regulated CCCH protein necessary for DNA lesion-induced S-phase arrest. Biology open 19 29449217
2022 ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peripartum cardiomyopathy in mice. The Journal of clinical investigation 18 35316214
2011 Mutation in the RNA binding protein TIS11D/ZFP36L2 is associated with the pathogenesis of acute leukemia. International journal of oncology 16 21109922
2021 Transcriptomics Reveals the ERF2-bHLH2-CML5 Module Responses to H2S and ROS in Postharvest Calcium Deficiency Apples. International journal of molecular sciences 15 34884817
2024 Regulation of IFN-γ production by ZFP36L2 in T cells is time-dependent. European journal of immunology 14 38980256
2018 ZFP36L2, a novel AML1 target gene, induces AML cells apoptosis and inhibits cell proliferation. Leukemia research 14 29518627
2010 A computational study of RNA binding and specificity in the tandem zinc finger domain of TIS11d. Protein science : a publication of the Protein Society 14 20506496
2006 Studies on transcriptional regulation of endogenous genes by ERF2 transcription factor in tobacco cells. Plant & cell physiology 14 16452120
2023 The RNA binding proteins ZFP36L1 and ZFP36L2 are dysregulated in airway epithelium in human and a murine model of asthma. Frontiers in cell and developmental biology 11 37928904
2017 Impact of RNA structure on ZFP36L2 interaction with luteinizing hormone receptor mRNA. RNA (New York, N.Y.) 9 28455422
2023 A novel homozygous variant in ZFP36L2 cause female infertility due to oocyte maturation defect. Clinical genetics 8 37211617
2021 Silencing of ZFP36L2 increases sensitivity to temozolomide through G2/M cell cycle arrest and BAX mediated apoptosis in GBM cells. Molecular biology reports 7 33590411
2023 TREC mediated oncogenesis in human immature T lymphoid malignancies preferentially involves ZFP36L2. Molecular cancer 6 37430263
2022 Sequence and tissue targeting specificity of ZFP36L2 reveals Elavl2 as a novel target with co-regulation potential. Nucleic acids research 6 35380695
2021 ZFP36L2 Role in Thyroid Functionality. International journal of molecular sciences 6 34502288
2015 Probing the structural and dynamical effects of the charged residues of the TZF domain of TIS11d. Biophysical journal 6 25809263
2024 Identification of novel compound heterozygous ZFP36L2 variants implicated in oocyte maturation defects and female infertility. Journal of assisted reproduction and genetics 4 38829516
2024 Variants in NLRP2 and ZFP36L2, non-core components of the human subcortical maternal complex, cause female infertility with embryonic development arrest. Molecular human reproduction 4 39178021
2022 Targeted Re-Sequencing of the 2p21 Locus Identifies Non-Syndromic Cleft Lip Only Novel Susceptibility Gene ZFP36L2. Frontiers in genetics 4 35242166
2025 The zinc finger protein ZFP36L2 inhibits flavivirus infection via the 5'-3' XRN1-mediated RNA decay pathway in the replication complexes. Journal of biomedical science 3 39972499
2024 ZFP36L1 and ZFP36L2 reduce cyclin D1 expression by decreasing expression of E2F1 and long 3'UTR isoform of CCND1 transcripts. Molecular and cellular biochemistry 3 39110278
2023 Circ_0003789 Knockdown Inhibits Tumor Progression by miR-429/ZFP36L2 Axis in Gastric Cancer. Biochemical genetics 3 37962691
2025 Large-scale multiomic analysis identifies non-coding somatic driver mutations and nominates ZFP36L2 as a driver gene for pancreatic ductal adenocarcinoma. Gut 2 41062181
2023 MiR-520d-3p suppresses the proliferation and epithelial-mesenchymal transition of cervical cancer cells by targeting ZFP36L2. Heliyon 2 37600385
2025 Combined Deletion of ZFP36L1 and ZFP36L2 Drives Superior Cytokine Production in T Cells at the Cost of Cell Fitness. European journal of immunology 1 40249077
2024 Genetic association and functional validation of ZFP36L2 in non-syndromic orofacial cleft subtypes. Journal of human genetics 1 38321215
2024 Large-scale multi-omic analysis identifies noncoding somatic driver mutations and nominates ZFP36L2 as a driver gene for pancreatic ductal adenocarcinoma. medRxiv : the preprint server for health sciences 1 39371173
2023 The RNA-Binding Proteins OAS1, ZFP36L2, and DHX58 Are Involved in the Regulation of CD44 mRNA Splicing in Colorectal Cancer Cells. Bulletin of experimental biology and medicine 1 37336810
2019 Author Correction: ZFP36L1 and ZFP36L2 inhibit cell proliferation in a cyclin D-dependent and p53-independent manner. Scientific reports 1 31745208
2026 RNA-binding proteins Zfp36l1 and Zfp36l2 protect against premature thymic involution. Cellular & molecular immunology 0 41840035
2026 ZFP36L2 is an interferon β -induced inhibitor that restricts the nuclear export of HIV-1 transcripts. Nature communications 0 41932956
2026 Deficiency of ZFP36L1 and ZFP36L2 impairs liver homeostasis and initiates cholestatic liver injury. Hepatology communications 0 42008774
2024 Identification of deleterious non-synonymous single nucleotide polymorphisms in the mRNA decay activator ZFP36L2. RNA biology 0 39668715

Missed literature

Know a paper Affinage missed for ZFP36L2? Flag it for the maintainers and the community.

No submissions yet.