Lin28, a major translation reprogramming factor, gains access to YB-1-packaged mRNA through its cold-shock domain

Abstract

The RNA-binding protein Lin28 (Lin28a) is an important pluripotency factor that reprograms translation and promotes cancer progression. Although Lin28 blocks let-7 microRNA maturation, Lin28 also binds to a large set of cytoplasmic mRNAs directly. However, how Lin28 regulates the processing of many mRNAs to reprogram global translation remains unknown. We show here, using a structural and cellular approach, a mixing of Lin28 with YB-1 (YBX1) in the presence of mRNA owing to their cold-shock domain, a conserved β-barrel structure that binds to ssRNA cooperatively. In contrast, the other RNA binding-proteins without cold-shock domains tested, HuR, G3BP-1, FUS and LARP-6, did not mix with YB-1. Given that YB-1 is the core component of dormant mRNPs, a model in which Lin28 gains access to mRNPs through its co-association with YB-1 to mRNA may provide a means for Lin28 to reprogram translation. We anticipate that the translational plasticity provided by mRNPs may contribute to Lin28 functions in development and adaptation of cancer cells to an adverse environment.

YB-1 unwinds mRNA secondary structures in vitro and negatively regulates stress granule assembly in HeLa cells

“…On the other hand, YB-1 preserves RNA secondary structure, compacts mRNAs to maintain their dormancy, and positively regulates the formation of mRNA-rich condensates in some tissues. Precise spatio-temporal regulation of YB-1 mRNP activation can possibly be orchestrated by posttranslational events in the CTD and CSD ( 27 , 34 , 67 ) and protein partners ( 36 , 54 ).…”

“…In proliferating cells, YB-1 is generally abundant ( 32 , 33 ) which may contradict the notion that it is a global inhibitor of mRNA translation. Cellular signaling, YB-1 post-translational modification ( 34 , 35 ), and/or protein partners such as Lin28 ( 36 ) may either facilitate translation in proliferating cells or maintain YB-1-packaged mRNA in a dormant state, as evidence in testis ( 37 ).…”

Lin28A/CENPE Promoting the Proliferation and Chemoresistance of Acute Myeloid Leukemia

“…For example, in a study on colorectal cancer, LIN28A was found to promote the development and progression of disease by regulating the expression of the mRNA GEFT ( 38 ). Moreover, LIN28A has been confirmed to have the capacity to stabilize and modulate the expression of various mRNAs, including YB-packaged mRNA, RAN, and HSBP1 mRNA in tumors ( 40 – 42 ). More interestingly, it has been shown that LIN28A participated in regulating the differentiation and cell cycle progression of AML cells ( 43 ).…”

“…Highly expressed LIN28A can serve as a potential oncogenic factor that contributes to the tumorigenesis, development, and migration of ovarian, breast, liver, and colon cancers (27)(28)(29)(30)(31)(32)(33). Mechanism-wise, LIN28A can modulate the translation of its targeted mRNA and restrain let-7 expression in the posttranscriptional level, which both depend on the LIN28A protein's RNA-binding motif (34)(35)(36)(37)(38)(39)(40)(41)(42). For example, in a study on colorectal cancer, LIN28A was found to promote the development and progression of disease by regulating the expression of the mRNA GEFT (38).…”

RNANetMotif: identifying sequence-structure RNA network motifs in RNA-protein binding sites

“…In the case of 4mer simulation, this loop-RNA contact served as an anchor and additional contacts were formed after certain RNA conformational changes. In a recent study, NMR and mutation studies indicated that K88, K89 (K98, K99 in LIN28A) play a role in electrostatic interactions with nucleic acids (83), and a recent study found a highly conserved Lys residue in YB1 protein (equivalent to K92 in Lin28B) is involved in ssDNA binding (84), as did the structural study of LIN28 on ssRNA nucleotides (72). Altogether, these evidences suggest that our graph-based approach is very effective in finding structure elements in RBP binding sites that are important in RBP-RNA recognition.…”