mRNA export through an additional cap-binding complex consisting of NCBP1 and NCBP3

Abstract

The flow of genetic information from DNA to protein requires polymerase-II-transcribed RNA characterized by the presence of a 5′-cap. The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. Here we show that NCBP1, but not NCBP2, is required for cell viability and poly(A) RNA export. We identify C17orf85 (here named NCBP3) as a cap-binding protein that together with NCBP1 forms an alternative CBC in higher eukaryotes. NCBP3 binds mRNA, associates with components of the mRNA processing machinery and contributes to poly(A) RNA export. Loss of NCBP3 can be compensated by NCBP2 under steady-state conditions. However, NCBP3 becomes pivotal under stress conditions, such as virus infection. We propose the existence of an alternative CBC involving NCBP1 and NCBP3 that plays a key role in mRNA biogenesis.

The role of TREX in gene expression and disease

“…NCBP3 knockdown leads to a clear nuclear accumulation of mRNA, establishing its role in mRNA export. It also appears to act preferentially during times of stress such as during viral infection [46]. The earlier observation that NCBP3 associates with TREX [14] may account for the role of NCBP3 in mRNA export, by providing the means to ensure TREX recruitment to the 5′ end of mRNAs and promoting efficient mRNA export in times of stress.…”

NCBP1 promotes the development of lung adenocarcinoma through up‐regulation of CUL4B

“…Cap‐binding complex was first recognized in HeLa cells for its ability to bind to the N7‐methylated guanine (m 7 G) ‘cap structure’ of newly transcribed mRNA and to orchestrate downstream RNA biogenesis processes such as nuclear‐cytoplasmic transport and recruitment of translation factors in the cytoplasm . The nuclear CBC is highly conserved, from plants to humans, and consists of a heterodimer formed by nuclear cap‐binding proteins, NCPB1, NCPB2 and NCBP3, the first two of which are also referred to in the literature as cap‐binding protein 80 (CBP80) and CBP20, respectively, based on their molecular weights, whereas NCBP3 (as known as C17orf85) is a recently identified novel cap‐binding protein . NCBP2 and NCBP3 bind directly to the RNA cap, and NCBP1 stabilizes NCBP2 or NCBP3 and promotes post‐transcriptional processes.…”

The Diverse Requirements of ARS2 in nuclear cap-binding complex-dependent RNA Processing

“…Interestingly, both NCBP3 and CBP20 bound many common factors, including ARS2, and only double KD of NCBP3 and CBP20 significantly disrupted mRNA export, suggesting some redundancy between the two complexes; however, NCBP3 preferentially interacted with TREX, while CBP20 exclusively bound snRNA and PHAX, indicating these two complexes may have developed specialized functions in mRNA and snRNA export [122] . Deciphering the roles of this alternative CBC as well as how it interacts with ARS2 will be an exciting area of research.…”

“…Recently, an alternative mammalian CBC was discovered where NCBP3 could bind CBP80 and the m7G cap in place of CBP20 [122] . Interestingly, both NCBP3 and CBP20 bound many common factors, including ARS2, and only double KD of NCBP3 and CBP20 significantly disrupted mRNA export, suggesting some redundancy between the two complexes; however, NCBP3 preferentially interacted with TREX, while CBP20 exclusively bound snRNA and PHAX, indicating these two complexes may have developed specialized functions in mRNA and snRNA export [122] .…”