The RNA-editing Enzyme APOBEC1 Requires Heterogeneous Nuclear Ribonucleoprotein Q Isoform 6 for Efficient Interaction with Interleukin-8 mRNA

Shimizu, Yuko; Nishitsuji, Hironori; Marusawa, Hiroyuki; Ujino, Saneyuki; Takaku, Hiroshi; Shimotohno, Kunitada

doi:10.1074/jbc.m114.563221

Cited by 12 publications

(14 citation statements)

References 27 publications

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“…Recently, hnRNP Q6 was identified as an APOBEC1-interacting protein that is required for APOBEC1's association with IL-8 mRNA (44). In that study, the complex was involved in IL-8 mRNA stabilization by an as yet unknown mechanism, suggesting that the APOBEC1-hnRNP Q6 complex may have a novel function associated with RNA processing rather than with C-to-U editing.…”

Section: Discussionmentioning

confidence: 75%

Identification of DNA cleavage- and recombination-specific hnRNP cofactors for activation-induced cytidine deaminase

Begum

Mondal

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Activation-induced cytidine deaminase (AID) is essential for antibody class switch recombination (CSR) and somatic hypermutation (SHM). AID originally was postulated to function as an RNAediting enzyme, based on its strong homology with apolipoprotein B mRNA-editing enzyme, catalytic polypeptide 1 (APOBEC1), the enzyme that edits apolipoprotein B-100 mRNA in the presence of the APOBEC cofactor APOBEC1 complementation factor/APOBEC complementation factor (A1CF/ACF). Because A1CF is structurally similar to heterogeneous nuclear ribonucleoproteins (hnRNPs), we investigated the involvement of several well-known hnRNPs in AID function by using siRNA knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated disruption. We found that hnRNP K deficiency inhibited DNA cleavage and thereby induced both CSR and SHM, whereas hnRNP L deficiency inhibited only CSR and somewhat enhanced SHM. Interestingly, both hnRNPs exhibited RNA-dependent interactions with AID, and mutant forms of these proteins containing deletions in the RNA-recognition motif failed to rescue CSR. Thus, our study suggests that hnRNP K and hnRNP L may serve as A1CF-like cofactors in AID-mediated CSR and SHM.class switch recombination | somatic hypermutation | activation-induced cytidine deaminase | B cell | IgH A ntigen-stimulated mature B cells express activation-induced cytidine deaminase (AID), an essential enzyme for somatic hypermutation (SHM) and class switch recombination (CSR) at the Ig locus (1, 2). AID induces DNA breaks at the variable (V) and switch (S) regions during SHM and CSR, respectively. Most of the mutations produced during SHM are introduced by errorprone DNA synthesis during single-strand break (SSB) repair (3, 4). In contrast, CSR requires the conversion of SSBs to doublestrand breaks (DSBs), followed by recombination between two DSB ends located in the donor and acceptor S regions (5, 6). The entire process of CSR is accomplished through elaborate DNArepair processes involving S-S synapse formation and end-joining.The mechanism by which AID functions differently in DNA cleavage and recombination at different loci remains unclear. Functional studies of a large number of AID mutants revealed that the N-terminal AID mutations impair SHM and CSR, indicating that the AID N terminus, which also possesses a bipartite nuclear-localization signal, is required for DNA cleavage in both SHM and CSR (7-9). On the other hand, C-terminal AID mutations suppressed the recombination activity of CSR but had no effect on SHM, indicating that the C terminus of AID, which contains a nuclear-export signal, is required for the recombination activity associated specifically with CSR (7, 9, 10). Indeed, recent studies showed that defects in the AID C terminus compromise DNA end-joining and S-S synapse formation without perturbing DNA breakage at either the V or S region (11, 12), also suggesting a specific role for the AID C terminus in the recombination step of CSR. Given AID's small size (198 resi...

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Section: Discussionmentioning

confidence: 75%

Identification of DNA cleavage- and recombination-specific hnRNP cofactors for activation-induced cytidine deaminase

Begum

Mondal

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Notable is hnRNPQ because it was identified by the HIV-1, SNV and RSV 5’ UTRs and from human and chicken cell lineages. Also known as SYNCRIP and the mouse minute virus NS1-associated protein (NASP), hnRNPQ and has been recognized to participate in the regulation of translation and miRNA-mediated repression of specific mRNAs, and influencing the activity of APOBEC1, a homolog of APOBEC3G (Lau et al, 2001; Shimizu et al, 2014; Svitkin et al, 2013). hnRNPQ plays dual roles in HCV, influencing viral RNA replication and translation (Liu et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

HIV-1 and two avian retroviral 5′ untranslated regions bind orthologous human and chicken RNA binding proteins

Stake

Singh

et al. 2015

Virology

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Essential host cofactors in retrovirus replication bind cis-acting sequences in 5’untranslated region (UTR). Although host RBPs are crucial to all aspects of virus biology, elucidating their roles in replication remains a challenge to the field. Here RNA affinity-coupled-proteomics generated a comprehensive, unbiased inventory of human and avian RNA binding proteins (RBPs) co-isolating with 5’UTRs of HIV-1, spleen necrosis virus and Rous sarcoma virus. Applying stringent biochemical and statistical criteria, we identified 185 RBP; 122 were previously implicated in retrovirus biology and 63 are new to the 5’UTR proteome. RNA electrophoretic mobility assays investigated paralogs present in the common ancestor of vertebrates and one hnRNP was identified central node to the biological process-anchored networks of HIV-1, SNV, and RSV 5’ UTR-proteomes. This comprehensive view of the host constituents of retroviral RNPs is broadly applicable to investigation of viral replication and antiviral response in both human and avian cell lineages.

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“…A1 not only associates with A1CF or RBM47, but also interacts with other RBPs and hnRNPs (AB, Q, C, and K) (17,(51)(52)(53)(54). These cofactors regulate APOB mRNA editing, either positively or negatively, and IL8 mRNA stability (54). The functional relevance of all of the A1-associated RBPs is not yet fully understood, but they may participate in a variety of RNA-processing events by A1.…”

Section: Discussionmentioning

confidence: 99%

“…The extreme C terminus of A1 is also important for dimerization; the A1 dimer associates with the cofactor A1CF and forms the functional APOB-mRNA editing complex (38,39). A1 not only associates with A1CF or RBM47, but also interacts with other RBPs and hnRNPs (AB, Q, C, and K) (17,(51)(52)(53)(54). These cofactors regulate APOB mRNA editing, either positively or negatively, and IL8 mRNA stability (54).…”

Section: Discussionmentioning

confidence: 99%

Functional requirements of AID’s higher order structures and their interaction with RNA-binding proteins

Mondal

Begum

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Activation-induced cytidine deaminase (AID) is essential for the somatic hypermutation (SHM) and class-switch recombination (CSR) of Ig genes. Although both the N and C termini of AID have unique functions in DNA cleavage and recombination, respectively, during SHM and CSR, their molecular mechanisms are poorly understood. Using a bimolecular fluorescence complementation (BiFC) assay combined with glycerol gradient fractionation, we revealed that the AID C terminus is required for a stable dimer formation. Furthermore, AID monomers and dimers form complexes with distinct heterogeneous nuclear ribonucleoproteins (hnRNPs). AID monomers associate with DNA cleavage cofactor hnRNP K whereas AID dimers associate with recombination cofactors hnRNP L, hnRNP U, and Serpine mRNA-binding protein 1. All of these AID/ribonucleoprotein associations are RNA-dependent. We propose that AID's structurespecific cofactor complex formations differentially contribute to its DNA-cleavage and recombination functions., which is expressed in antigen-stimulated mature B cells, is essential for Ig somatic hypermutation (SHM) and class-switch recombination (CSR) (1, 2). AID induces DNA breaks at the variable (V) and switch (S) regions during SHM and CSR, respectively (3, 4). Although both processes are initiated by AID-induced DNA cleavage, point mutations at the V region are executed mostly by error-prone DNA repair whereas CSR is accomplished by recombination of cleaved ends at donor and acceptor S regions (5, 6). However, the detailed mechanisms by which AID carries out the two mechanistically distinct functions for SHM and CSR have yet to be uncovered (7). Studies on AID mutants revealed that AID's N-and C-terminal domains are distinctly required for its DNA-cleavage and recombination functions, respectively (8-10). Mutations at the N terminus of AID impair SHM as well as CSR whereas those at the C terminus abrogate CSR only and show increased SHM activity. Recent studies demonstrated that the CSR process after DNA cleavage, including the synapsis formation between cleaved ends, is impaired with the C-terminally defective AID, indicating that AID's C terminus confers a CSR-specific recombination function, independent of AID's DNA cleavage function, by an unknown mechanism (11,12).AID belongs to the APOBEC (apolipoprotein B mRNA-editing enzyme catalytic polypeptide) family of cytidine deaminases (CDDs) and shows high sequence homology with APOBEC1 (A1) (1,13,14), which edits apolipoprotein B (APOB) mRNA. The APOB mRNA editing ability of A1 is highly dependent on its cofactors, A1CF/ACF (15, 16) and RBM47 (17), both of which belong to the heterogeneous nuclear ribonucleoprotein (hnRNP) family. Recently, two A1CF-like hnRNPs, hnRNP K and hnRNP L, were identified as the cofactors of AID and found to be involved in the cleavage and recombination of DNA, respectively (18). Because the N and C termini of AID differentially regulate two functions of AID-cleavage and recombination, respectivelywe speculated that the AID termini would be critical...

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The RNA-editing Enzyme APOBEC1 Requires Heterogeneous Nuclear Ribonucleoprotein Q Isoform 6 for Efficient Interaction with Interleukin-8 mRNA

Cited by 12 publications

References 27 publications

Identification of DNA cleavage- and recombination-specific hnRNP cofactors for activation-induced cytidine deaminase

Identification of DNA cleavage- and recombination-specific hnRNP cofactors for activation-induced cytidine deaminase

HIV-1 and two avian retroviral 5′ untranslated regions bind orthologous human and chicken RNA binding proteins

Functional requirements of AID’s higher order structures and their interaction with RNA-binding proteins

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