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  • Numerous investigators have shown that RACK has several impo

    2023-09-14

    Numerous investigators have shown that RACK1 has several important, possibly related, roles in mRNA splicing and in translation. RACK1 interacts directly with specific components of the 40S ribosomal subunit (specifically, the 18S rRNA and ribosomal proteins rpS16e, rpS17e, and rpS3e [new names: uS9, eS17 and uS3, respectively]; refs. [59], [60]). It has been suggested that RACK1 may recruit signaling molecules, such as PKC and JNK, to the ribosome [61], [62], although the precise function(s) of ribosomal RACK in complex eukaryotes remain an active area of investigation [3]. RACK1 also interacts with the HABP4 protein (synonym: Ki-1/57), which is involved in mRNA metabolism [63], [64]. HABP4 interacts with the chromo-helicase-DNA-binding domain protein 3 (CHD-3), a nuclear protein involved in chromatin remodeling and transcription regulation [65]. HABP4 is also a substrate of protein arginine N-methyltransferase 1 (PRMT1), which methylates two discreet regions on HABP4, both approximately 21 Digoxin in length and consisting of repeats of the sequence RGG and/or RGR [66], [67]. HABP4 plays an important role in mRNA splicing, which is mediated by its interaction with the splicing proteins hnRNPQ and SFRS9 [68], [69]. It may also play a role in mRNA translation, as one group has shown that it interacts with ribosomal protein L38, although the physiologic significance of this finding is not clear [70]. One group has also shown that RACK1 interacts with the polyA-binding protein LARP4 [71]. SERBP1 (synonyms: CGI-55, CHD3IP, HABP4L, PAI-RBP1), the focus of the present study, is an mRNA-binding protein [72]. SERBP1 binds to a 134-nucleotide cyclic nucleotide-responsive sequence (CRS) located near the 3′ end of several mRNAs, most notably that encoding type-1 plasminogen activator inhibitor (PAI-1; refs. [72], [73], [74]). Studies in a number of cell lines that shown that elevation of intracellular cAMP levels markedly increases the rate of degradation of PAI-1 mRNA, which has been shown to be mediated by SERBP1 [73], [75]. Like HABP4, SERBP1 binds to CHD-3, which for SERBP1 involves two separate regions, located in its N- and C-termini [76], [77]. SERBP1 has also been shown to bind to the RNA splicing component U2AF [78]. These data implicate SERBP1 in several nuclear functions, separate from its action on mRNA. Also like HABP4, SERBP1 is a substrate for PRMT1-mediated arginine methylation, which may regulate the nuclear-cytoplasmic distribution of the protein [79], [80]. SERBP1 and HABP4 target similar mRNA populations in cells, clearly suggesting some overlap in their physiological functions [81]. SERBP1 also interacts with progesterone receptor membrane component 1 (PGRMC1), linking it to progesterone-signaling pathways [82]. Given the similarities between SERBP1 and HABP4 that have been reported to date, it would not be unexpected that they might share protein partners. As discussed above, both interact with CHD-3 [65], [76], [77]. In the present study, we report that SERBP1, like HABP4, interacts with RACK1 in 2-hybrid assays. We also show that the interaction of SERBP1 with RACK1 requires an extensive region Digoxin located in the C-terminal third of the SERBP1 protein. We also show that a large surface on RACK1, which overlaps substantially that needed for RACK1 to interact with PDE4D5, is necessary for it to interact with SERBP1. Our data provide additional impetus to search for additional functional roles of RACK1 in nuclear processes, such as chromatin remodeling, and possibly in mRNA splicing and stability.
    Materials and methods
    Results
    Discussion SERBP1 has homology to several related proteins, most notably HABP4 (synonym: Ki-1/57), a protein that also interacts with RNA and has several potential nuclear functions. However, SERBP1 differs from HABP4 in that it interacts avidly with highly-specific regions of sequence in the 3′ termini of several mRNAs, regulating their stability in response to specific stimuli [72], [73], [74]. Both SERBP1 and HABP4 have 2 sites for arginine methylation by PRMT (Fig. 1, Fig. 3) and interact with CHD-3, a nuclear protein involved in chromatin remodeling and transcription regulation [65], [76], [77]. These common functions may provide an explanation for their significant amino acid sequence homology (Fig. 3); however, the precise region(s) of the 2 proteins responsible for many of their functions are not known, especially in the absence of structural clues. HABP4 is felt to be an intrinsically-disordered protein [94]; to the best of our knowledge, there is no structural data on SERBP1.