The tandem zinc finger RNA binding domain of members of the tristetraprolin protein family

Abstract

Tristetraprolin (TTP), the prototype member of the protein family of the same name, was originally discovered as the product of a rapidly inducible gene in mouse cells. Development of a knockout (KO) mouse established that absence of the protein led to a severe inflammatory syndrome, due in part to elevated levels of tumor necrosis factor (TNF). TTP was found to bind directly and with high affinity to specific AU‐rich sequences in the 3′‐untranslated region of the TNF mRNA. This initial binding led to promotion of TNF mRNA decay and inhibition of its translation. Many additional TTP target mRNAs have since been identified, some of which are cytokines and chemokines involved in the inflammatory response. There are three other proteins in the mouse with similar activities and domain structures, but whose KO phenotypes are remarkably different. Moreover, proteins with similar domain structures and activities have been found throughout eukaryotes, demonstrating that this protein family arose from an ancient ancestor. The defining characteristic of this protein family is the tandem zinc finger (TZF) domain, a 64 amino acid sequence with many conserved residues that is responsible for the direct RNA binding. We discuss here many aspects of this protein domain that have been elucidated since the original discovery of TTP, including its sequence conservation throughout eukarya; its apparent continued evolution in some lineages; its functional dependence on many key conserved residues; its “interchangeability” among evolutionarily distant species; and the evidence that RNA binding is required for the physiological functions of the proteins. This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA‐Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

Ultrashort Wave Combined with Human Umbilical Cord Mesenchymal Stem Cell (HUC-MSC) Transplantation Inhibits NLRP3 Inflammasome and Improves Spinal Cord Injury via MK2/TTP Signalling Pathway

“…Its mechanism of action is related to inhibit the expression of MAPK-activated protein kinase 2 (MK2), which is involved in the regulation of cell cycle, cell migration, actin remodelling, and inflammation as a substrate of p38 MAPK. In inflammatory diseases, MK2 can activate the RNA binding protein tristetraprolin (TTP), a member of the zinc-finger protein family, thereby regulating the translation of TNF- α and inflammatory factors and promoting the relative expressions [ 14 , 15 ]. Meanwhile, TTP is a negative regulator of the NLRP3 inflammasome, inhibiting the expression of NLRP3 through target binding to the 3′-UTR region of NLRP3, speculating that MK2 might release the inhibition of the NLRP3 expression by TTP and increase the NLRP3 expression through phosphorylating TTP [ 16 ].…”

The Combined Regulation of Long Non-coding RNA and RNA-Binding Proteins in Atherosclerosis

“…The RNA-binding protein tristetraprolin (TTP, encoded by ZFP36) has been found early in eukaryotes (124). This was characterized by the RNA-binding tandem zinc finger (TZF) domain and often be associated with cancer, as well as other inflammatory diseases (101,(125)(126)(127). Its function is as a decay signal of RNA by binding to AREs, and adenylate/uridylate-rich RNA motifs (128).…”

Intrinsically disordered regions of Tristetraprolin and DCP2 directly interact to mediate decay of ARE-mRNA

“…This suggests that the TTP N-terminal activation domain is capable of mediating decay of ARE-RNA, independent of the C-terminal activation domain and the NIM-sequence therein. A TTP construct lacking the N-terminal activation domain was not tested in these assays as the nuclear export signal of TTP resides within its N-terminus (Phillips, Ramos et al 2002, Lai, Wells et al 2019, and its absence would render the protein incapable of localizing to the cytoplasm. Since TTPN interacts with the DCP2C-tail, we next proceeded to test if the ability of the TTP N-terminal domain to activate decay is dependent on DCP2.…”