lin28a

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000932 P-body	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: P-body localization mapped from the UniProt subcellular location (by similarity to human LIN28A). Reason: Mammalian Lin28 localizes to P-bodies through its CCHC domain. Plausible for the frog protein by conservation, but P-body residence is not where its let-7 or translational activity has been shown to operate; keep as non-core. Supporting Evidence: file:XENLA/lin28a/lin28a-uniprot.txt Cytoplasm, P-body PMID:17617744 Lin28 also localizes to cytoplasmic processing bodies, or P-bodies
GO:0000932 P-body	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: P-body localization transferred from human LIN28A (Q9H9Z2), which has IDA support. Reason: Correct transfer of a mammalian cell-biology observation; CCHC knuckles are conserved in Q8JHC4. Non-core location. Supporting Evidence: PMID:17617744 Lin28 also localizes to cytoplasmic processing bodies, or P-bodies PMID:12798299 These homologues are characterized by the LIN-28 protein's unusual pairing of RNA-binding motifs: a cold shock domain (CSD) and a pair of retroviral-type CCHC zinc knuckles
GO:0003676 nucleic acid binding	IEA GO_REF:0000002	MODIFY	Summary: Generic nucleic acid binding mapped from InterPro cold-shock/CSP_DNA-bd and CCHC zinc-knuckle signatures. Reason: Both Lin28 domains bind RNA: the CSD remodels the pre-let-7 terminal loop and the zinc knuckles bind the GGAG motif. The InterPro "CSP_DNA-bd" name reflects the bacterial cold-shock fold, not DNA binding by Lin28; there is no evidence that Lin28 binds DNA. Replace with RNA binding, which the gene also carries by ISS. Proposed replacements: RNA binding Supporting Evidence: file:XENLA/lin28a/lin28a-uniprot.txt The CCHC zinc fingers interact with the GGAG motif PMID:12798299 These homologues are characterized by the LIN-28 protein's unusual pairing of RNA-binding motifs: a cold shock domain (CSD) and a pair of retroviral-type CCHC zinc knuckles PMID:26447465 We demonstrate that lin28a binds to the terminal loop of pre-mir-363 with an affinity similar to that of let-7, and that this high affinity interaction requires to conserved a GGAG motif
GO:0003723 RNA binding	ISS GO_REF:0000024	ACCEPT	Summary: RNA binding transferred from human LIN28A. Reason: Core activity of every characterized Lin28 protein, and directly shown for the X. tropicalis lin28a ortholog, which binds pre-let-7g and pre-mir-363 terminal loops with sub-micromolar affinity. Supporting Evidence: PMID:26447465 We demonstrate that lin28a binds to the terminal loop of pre-mir-363 with an affinity similar to that of let-7, and that this high affinity interaction requires to conserved a GGAG motif file:XENLA/lin28a/lin28a-uniprot.txt RNA-binding protein that inhibits processing of pre-let-7 PMID:19703396 Lin28 recruits TUT4 to pre-let-7 by recognizing a tetra-nucleotide sequence motif (GGAG) in the terminal loop
GO:0003729 mRNA binding	IBA GO_REF:0000033	ACCEPT	Summary: mRNA binding inherited from the Lin-28 family ancestral node (PTN002919024), with experimental support from human, mouse, worm and fly members. Reason: Lin28 proteins associate with mRNPs and polysomes and bind specific mRNAs; the frog protein lies well within the clade and retains both RNA-binding domains. No evidence of divergence in Xenopus. Supporting Evidence: PMID:17617744 Lin28 binds mRNAs in the nucleus and accompanies them to ribosomes and P-bodies PMID:21247876 Lin28 may stimulate translation by actively recruiting RHA to polysomes PMID:12798299 These homologues are characterized by the LIN-28 protein's unusual pairing of RNA-binding motifs: a cold shock domain (CSD) and a pair of retroviral-type CCHC zinc knuckles
GO:0003729 mRNA binding	IEA GO_REF:0000118	ACCEPT	Summary: TreeGrafter transfer of mRNA binding from the same PANTHER family. Reason: Consistent with the IBA; duplicate of a correct annotation. Supporting Evidence: PMID:17617744 Lin28 binds mRNAs in the nucleus and accompanies them to ribosomes and P-bodies PMID:12798299 These homologues are characterized by the LIN-28 protein's unusual pairing of RNA-binding motifs: a cold shock domain (CSD) and a pair of retroviral-type CCHC zinc knuckles
GO:0003729 mRNA binding	ISS GO_REF:0000024	ACCEPT	Summary: mRNA binding transferred from human LIN28A. Reason: Consistent with the IBA and with the conserved domain architecture. Supporting Evidence: PMID:17617744 Lin28 binds mRNAs in the nucleus and accompanies them to ribosomes and P-bodies PMID:21247876 Lin28 may stimulate translation by actively recruiting RHA to polysomes
GO:0005634 nucleus	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Nucleus inherited from the Lin-28 family node. Reason: Lin28A is predominantly cytoplasmic and shuttles through the nucleus bound to RNA; LIN28B is the paralog with prominent nuclear action. Nuclear presence is real but not the main site of Lin28a function. Supporting Evidence: PMID:17617744 When both RNA-binding domains are mutated, Lin28 accumulates in the nucleus, suggesting that it normally shuttles from nucleus to cytoplasm bound to RNA file:XENLA/lin28a/lin28a-uniprot.txt Predominantly cytoplasmic file:XENLA/lin28a/lin28a-uniprot.txt Shuttle from the nucleus to
GO:0005634 nucleus	IEA GO_REF:0000118	KEEP AS NON CORE	Summary: TreeGrafter nucleus transfer. Reason: As for the IBA row: transit/shuttling location, not the main site of action. Supporting Evidence: PMID:17617744 When both RNA-binding domains are mutated, Lin28 accumulates in the nucleus, suggesting that it normally shuttles from nucleus to cytoplasm bound to RNA file:XENLA/lin28a/lin28a-uniprot.txt Shuttle from the nucleus to
GO:0005634 nucleus	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Nucleus transferred from human LIN28A. Reason: As for the IBA row. Supporting Evidence: PMID:17617744 When both RNA-binding domains are mutated, Lin28 accumulates in the nucleus, suggesting that it normally shuttles from nucleus to cytoplasm bound to RNA file:XENLA/lin28a/lin28a-uniprot.txt Predominantly cytoplasmic
GO:0005730 nucleolus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Nucleolus mapped from the UniProt subcellular location (by similarity to mouse Lin28a). Reason: Nucleolar localization has been reported for mammalian Lin28a; no frog data. Non-core. Supporting Evidence: file:XENLA/lin28a/lin28a-uniprot.txt Nucleus, nucleolus file:XENLA/lin28a/lin28a-uniprot.txt Predominantly cytoplasmic
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Cytoplasm inherited from the Lin-28 family node. Reason: Cytoplasm is where Lin28 blocks pre-let-7 processing (via TUT4 uridylation) and where it binds mRNAs. Core location. Supporting Evidence: PMID:18951094 the Lin28 proteins act mainly in the cytoplasm by inducing uridylation of precursor let-7 PMID:17617744 Lin28 is a conserved cytoplasmic protein file:XENLA/lin28a/lin28a-uniprot.txt Predominantly cytoplasmic
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Cytoplasm from combined automated methods (UniProt SubCell and TreeGrafter). Reason: Core location; duplicate of the IBA. Supporting Evidence: file:XENLA/lin28a/lin28a-uniprot.txt Predominantly cytoplasmic PMID:18951094 the Lin28 proteins act mainly in the cytoplasm by inducing uridylation of precursor let-7
GO:0005737 cytoplasm	ISS GO_REF:0000024	ACCEPT	Summary: Cytoplasm transferred from mouse Lin28a. Reason: Core location. Supporting Evidence: PMID:17617744 Lin28 is a conserved cytoplasmic protein file:XENLA/lin28a/lin28a-uniprot.txt Predominantly cytoplasmic
GO:0005737 cytoplasm	ISS GO_REF:0000024	ACCEPT	Summary: Cytoplasm transferred from human LIN28A. Reason: Core location. Supporting Evidence: PMID:18951094 the Lin28 proteins act mainly in the cytoplasm by inducing uridylation of precursor let-7 file:XENLA/lin28a/lin28a-uniprot.txt Predominantly cytoplasmic
GO:0005791 rough endoplasmic reticulum	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Rough ER mapped from the UniProt subcellular location (by similarity to mouse Lin28a). Reason: Mouse ES-cell Lin28a sits at the cytosolic face of the rough ER and represses translation of ER-destined mRNAs. A plausible conserved location for a cytoplasmic mRNA-binding protein, but no frog evidence and not the core let-7 mechanism. Supporting Evidence: file:XENLA/lin28a/lin28a-uniprot.txt localizes to peri-endoplasmic reticulum regions
GO:0005791 rough endoplasmic reticulum	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Rough ER transferred from mouse Lin28a. Reason: As for the IEA row. Supporting Evidence: file:XENLA/lin28a/lin28a-uniprot.txt localizes to peri-endoplasmic reticulum regions
GO:0008270 zinc ion binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Zinc ion binding mapped from the CCHC zinc-knuckle InterPro entries. Reason: The two retroviral-type CCHC knuckles coordinate zinc structurally, so the term is correct, but it is a cofactor/structural feature of the RNA-binding domain rather than the functional activity. Supporting Evidence: PMID:12798299 These homologues are characterized by the LIN-28 protein's unusual pairing of RNA-binding motifs: a cold shock domain (CSD) and a pair of retroviral-type CCHC zinc knuckles file:XENLA/lin28a/lin28a-uniprot.txt The CCHC zinc fingers interact with the GGAG motif
GO:0010494 cytoplasmic stress granule	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Stress granule mapped from the UniProt subcellular location. Reason: Stress-induced relocalization in mammalian cells; not a core site of activity. Supporting Evidence: file:XENLA/lin28a/lin28a-uniprot.txt Cytoplasm, Stress granule PMID:17617744 Upon cellular stress, Lin28 locates to stress granules
GO:0010494 cytoplasmic stress granule	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Stress granule transferred from human LIN28A. Reason: As for the IEA row. Supporting Evidence: PMID:17617744 Upon cellular stress, Lin28 locates to stress granules
GO:0010629 negative regulation of gene expression	IEA GO_REF:0000117	ACCEPT	Summary: ARBA rule assigning negative regulation of gene expression. Reason: Broad but correct: Lin28 lowers let-7 output by blocking precursor processing and, in mammals, represses translation of ER-destined mRNAs. Broad IEA terms that are correct are kept. Note the frog early-embryo role may also include positive effects on some miRNAs (mir-17~92 family), which this term does not exclude. Supporting Evidence: PMID:18292307 Our results identify Lin28 as a negative regulator of miRNA biogenesis PMID:18951094 The uridylated pre-let-7 (up-let-7) fails Dicer processing and undergoes degradation PMID:26447465 Our data suggest a novel function for amphibian lin28 proteins as positive regulators of mir-17∼92 family miRNAs
GO:0019827 stem cell population maintenance	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Stem cell population maintenance transferred from human LIN28A, whose IMP comes from knockdown in cultured cells lowering stem cell markers. Reason: Judged against frog evidence: Xenopus lin28 is expressed in transient pluripotent blastula cells, and compound lin28a/lin28b knockdown impairs their response to FGF and activin/nodal mesoderm inducers rather than depleting a self-renewing population; later, overexpression delays metamorphosis. Neither shows maintenance of a stem cell population. The human source is itself a culture marker readout. In chick, Lin28a holds neural crest cells in a multipotent state through let-7 suppression, which is the closest real case, but there is no frog counterpart. Were frog evidence found, that role would belong under the proposed neural crest progenitor maintenance term (a child of this one), not this broad parent. Not wrong for mammals; an over-reach for frog. Supporting Evidence: PMID:19703396 Knockdown of TUT4 and Lin28 reduces the level of stem cell markers, suggesting that they are required for stem cell maintenance PMID:23344711 the ability of pluripotent cells from the embryo to respond to the FGF and activin/nodal-like mesoderm-inducing pathways is compromised following inhibition of lin28 function PMID:28359807 Lin28 overexpression before activation of TH signaling delays metamorphosis and inhibits the expression of TH target genes PMID:30520734 high levels of Lin28a during early development are necessary for neural crest specification, while its subsequent downregulation is required for silencing of progenitor identity
GO:0031054 pre-miRNA processing	IBA GO_REF:0000033	MODIFY	Summary: Pre-miRNA processing inherited from the Lin-28 family node (worm, mouse, human members). Reason: The node placement is sound (the let-7 axis is conserved from C. elegans), but the term is the wrong relation: Lin28 does not convert pre-miRNA to mature miRNA; it blocks Dicer processing of pre-let-7 by recruiting TUT4/7 for oligouridylation. The precise term, carried by human LIN28A by IDA, is negative regulation of pre-miRNA processing. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002919024 SUPPORTS TRANSFER Lin-28 family ancestral node. The let-7 regulatory function is correctly inherited by Xenopus lin28a, but the extant experimental evidence (human, mouse, worm) shows a regulator that blocks processing, not a participant in the conversion; negative regulation of pre-miRNA processing is the inherited role. Proposed replacements: negative regulation of pre-miRNA processing Supporting Evidence: PMID:18292307 Our results identify Lin28 as a negative regulator of miRNA biogenesis PMID:19703396 Lin28 recruits TUT4 to pre-let-7 by recognizing a tetra-nucleotide sequence motif (GGAG) in the terminal loop PMID:18951094 The uridylated pre-let-7 (up-let-7) fails Dicer processing and undergoes degradation file:XENLA/lin28a/lin28a-deep-research-falcon.md LIN28A binds and recruits; TUT4/TUT7 catalyze uridine addition
GO:0031054 pre-miRNA processing	IEA GO_REF:0000118	MODIFY	Summary: TreeGrafter transfer of pre-miRNA processing. Reason: As for the IBA row: Lin28 is a negative regulator, not a processing component. Proposed replacements: negative regulation of pre-miRNA processing Supporting Evidence: PMID:18292307 Our results identify Lin28 as a negative regulator of miRNA biogenesis PMID:18951094 The uridylated pre-let-7 (up-let-7) fails Dicer processing and undergoes degradation
GO:0031054 pre-miRNA processing	ISS GO_REF:0000024	MODIFY	Summary: Pre-miRNA processing transferred from human LIN28A. Reason: As for the IBA row. Proposed replacements: negative regulation of pre-miRNA processing Supporting Evidence: PMID:19703396 Lin28 recruits TUT4 to pre-let-7 by recognizing a tetra-nucleotide sequence motif (GGAG) in the terminal loop PMID:18951094 The uridylated pre-let-7 (up-let-7) fails Dicer processing and undergoes degradation
GO:2000767 positive regulation of cytoplasmic translation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Positive regulation of cytoplasmic translation transferred from human LIN28A (RNA helicase A recruitment to polysomes). Reason: A real mammalian Lin28 activity, carried by the C-terminal region conserved in the frog protein, but untested in Xenopus. In frog, a C-terminally truncated Lin28a that cannot engage RHA still delays metamorphosis, so the documented frog developmental role does not depend on translational enhancement. Supporting Evidence: PMID:21247876 Lin28 may stimulate translation by actively recruiting RHA to polysomes PMID:31397023 indicating that the translational regulation domain is not required to inhibit the HPT axis
GO:0070883 pre-miRNA binding	ISS PMID:26447465 lin28 proteins promote expression of 17∼92 family miRNAs dur...	NEW	Summary: Xenopus lin28a binds the terminal loops of pre-let-7g and pre-mir-363 through a GGAG motif, with sub-micromolar affinity. Reason: The specific RNA-binding activity of Lin28 is recognition of pre-miRNA terminal loops. This was shown directly for the X. tropicalis lin28a ortholog of Q8JHC4 (recombinant protein and embryo-translated lin28a in EMSA), and matches the human/mouse mechanism. More informative than generic RNA binding; human LIN28A carries it by IDA. Supporting Evidence: PMID:26447465 We demonstrate that lin28a binds to the terminal loop of pre-mir-363 with an affinity similar to that of let-7, and that this high affinity interaction requires to conserved a GGAG motif file:XENLA/lin28a/lin28a-uniprot.txt The CCHC zinc fingers interact with the GGAG motif PMID:19703396 Lin28 recruits TUT4 to pre-let-7 by recognizing a tetra-nucleotide sequence motif (GGAG) in the terminal loop

Gene Description

Existing Annotations Review

Core Functions

Cytoplasmic pre-miRNA-binding protein that recognizes GGAG-containing terminal loops (pre-let-7 and, in frog, pre-mir-363) through its cold-shock domain and CCHC zinc knuckles, and suppresses let-7 biogenesis by recruiting TUT4/7 to oligouridylate pre-let-7 so that Dicer cannot process it.

Sequence-selective mRNA-binding protein in cytoplasmic mRNPs; in mammals it enhances translation of selected mRNAs by recruiting RNA helicase A to polysomes (not yet shown in frog).

References

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