RNA binding protein SAMD4: current knowledge and future perspectives

Abstract

SAMD4 protein family is a class of novel RNA-binding proteins that can mediate post-transcriptional regulation and translation repression in eukaryotes, which are highly conserved from yeast to humans during evolution. In mammalian cells, SAMD4 protein family consists of two members including SAMD4A/Smaug1 and SAMD4B/Smaug2, both of which contain common SAM domain that can specifically bind to different target mRNAs through stem-loop structures, also known as Smaug recognition elements (SREs), and regulate the mRNA stability, degradation and translation. In addition, SAMD4 can form the cytoplasmic mRNA silencing foci and regulate the translation of SRE-containing mRNAs in neurons. SAMD4 also can form the cytosolic membrane-less organelles (MLOs), termed as Smaug1 bodies, and regulate mitochondrial function. Importantly, many studies have identified that SAMD4 family members are involved in various pathological processes including myopathy, bone development, neural development, and cancer occurrence and progression. In this review, we mainly summarize the structural characteristics, biological functions and molecular regulatory mechanisms of SAMD4 protein family members, which will provide a basis for further research and clinical application of SAMD4 protein family.

Effect of RNA m6A methyltransferase activation by a low molecular weight compound on anxiety- and depression-related behaviours, monoamine neurochemistry and striatal gene expression in the rat

“…For example, Galns and Samd4a have been implicated in neuronal viability and plasticity; Galns that encodes a lysosomal exohydrolase has been considered a gene related to Parkinson's disease (Wettergren et al, 2012) and Samd4a is a RNA binding protein that can bind to a variety of target mRNAs through stem-loop structures, also known as Smaug recognition elements (SREs). Notably, Samd4a can regulate the mRNA stability, degradation and translation (Wang and Zhang, 2023). Fgr (Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog) and Psmb9 (proteasome subunit beta type-9), two innate immunity genes, both of which were affected by CHMA1004 treatment, each were recently associated with specific genetic forms of Parkinson's disease (Shani et al, 2023).…”

RNA-binding proteins in bone pathophysiology

“…SAMD4 is an RBP with the role of protein translational repressor. It is mostly involved in the regulation of post-transcription events, including mRNA stability, and translational repression during early bone embryonic development ( Wang and Zhang, 2023 ). In vivo experiments in mice ( Niu et al, 2017 ) with a depletion of the Samd4 gene, have shown profound defects in both skeleton development and bone mass; compared to WT mice, KO Samd4 mice were characterized by impaired bone ossification and mineralization.…”

“…Primary osteoblasts collected from both KO Samd4, cultured under osteoblast differentiation medium, showed impaired of both early and late osteoblast differentiation when compared to those from WT mice. SAMD4 acts by inhibiting the translation of Mitogen-inducible gene 6 (Mig6) protein, a non-kinase scaffolding adaptor strongly expressed in osteoblasts, through binding the 3′UTR ( Staal et al, 2014 ; Wang and Zhang, 2023 ).…”

Dynamic mRNA stability changes buffer transcriptional activation during neuronal differentiation and are regulated by RNA binding proteins

“…SAMD4A, also known as Smaug1 in Drosophila, is a conserved RBP encoded by the SAMD4A gene 52 . Accumulating evidence highlighted the importance of SAMD4A in cell differentiation and developmental diseases 53 . For instance, depletion of SAMD4A leads to developmental defects in mice such as delayed bone development and reduced osteogenesis by inhibiting the translation of Mig6 32 .…”