Abstract:a b s t r a c t H-REV107-like family proteins TIG3 and H-REV107 are class II tumor suppressors. Here we report that the C-terminal domains (CTDs) of TIG3 and H-REV107 can induce HeLa cell death independently. The N-terminal domain (NTD) of TIG3 enhances the cell death inducing ability of CTD, while NTD of H-REV107 plays an inhibitory role. The solution structure of TIG3 NTD is very similar to that of H-REV107 in overall fold. However, the CTD binding regions on NTD are different between TIG3 and H-REV107, whic… Show more
“…This type of 2A has a conserved H-NC box, and some versions have a putative transmembrane domain (Hughes and Stanway, 2000). These 2A proteins are related to the cellular H-rev107 family, the members of which are involved in the control of cell proliferation (Tsai et al, 2009; Wei et al, 2015). In addition, the H-NC box is involved in virus replication.…”
Section: Conserved Motifs and Functions Of Parechovirus-like 2amentioning
Among the few non-structural proteins encoded by the picornaviral genome, the 2A protein is particularly special, irrespective of structure or function. During the evolution of the Picornaviridae family, the 2A protein has been highly non-conserved. We believe that the 2A protein in this family can be classified into at least five distinct types according to previous studies. These five types are (A) chymotrypsin-like 2A, (B) Parechovirus-like 2A, (C) hepatitis-A-virus-like 2A, (D) Aphthovirus-like 2A, and (E) 2A sequence of the genus Cardiovirus. We carried out a phylogenetic analysis and found that there was almost no homology between each type. Subsequently, we aligned the sequences within each type and found that the functional motifs in each type are highly conserved. These different motifs perform different functions. Therefore, in this review, we introduce the structures and functions of these five types of 2As separately. Based on the structures and functions, we provide suggestions to combat picornaviruses. The complexity and diversity of the 2A protein has caused great difficulties in functional and antiviral research. In this review, researchers can find useful information on the 2A protein and thus conduct improved antiviral research.
“…This type of 2A has a conserved H-NC box, and some versions have a putative transmembrane domain (Hughes and Stanway, 2000). These 2A proteins are related to the cellular H-rev107 family, the members of which are involved in the control of cell proliferation (Tsai et al, 2009; Wei et al, 2015). In addition, the H-NC box is involved in virus replication.…”
Section: Conserved Motifs and Functions Of Parechovirus-like 2amentioning
Among the few non-structural proteins encoded by the picornaviral genome, the 2A protein is particularly special, irrespective of structure or function. During the evolution of the Picornaviridae family, the 2A protein has been highly non-conserved. We believe that the 2A protein in this family can be classified into at least five distinct types according to previous studies. These five types are (A) chymotrypsin-like 2A, (B) Parechovirus-like 2A, (C) hepatitis-A-virus-like 2A, (D) Aphthovirus-like 2A, and (E) 2A sequence of the genus Cardiovirus. We carried out a phylogenetic analysis and found that there was almost no homology between each type. Subsequently, we aligned the sequences within each type and found that the functional motifs in each type are highly conserved. These different motifs perform different functions. Therefore, in this review, we introduce the structures and functions of these five types of 2As separately. Based on the structures and functions, we provide suggestions to combat picornaviruses. The complexity and diversity of the 2A protein has caused great difficulties in functional and antiviral research. In this review, researchers can find useful information on the 2A protein and thus conduct improved antiviral research.
“…20 Recently, the conserved N-terminal NlpC/P60 domain of TIG3 was also found to exhibit calcium-independent phospholipase A1/2 activity, which indicated that TIG3 might be involved in the process of phospholipid metabolism. 12,39 Interestingly, the inhibitory effect on cell survival induced by the C-terminal domain must be independent of the phospholipase A1/2 activity. 39 Based on these findings, we suspect that TIG3 may not provide the tumor-suppressing activity through the mechanism of subcellular localization, but acts as a phospholipid-metabolizing enzyme on the cellular context of GBM.…”
Section: Discussionmentioning
confidence: 99%
“…12,39 Interestingly, the inhibitory effect on cell survival induced by the C-terminal domain must be independent of the phospholipase A1/2 activity. 39 Based on these findings, we suspect that TIG3 may not provide the tumor-suppressing activity through the mechanism of subcellular localization, but acts as a phospholipid-metabolizing enzyme on the cellular context of GBM. Moreover, calcium-independent phospholipase A2 enzymes have been implicated in tumorigenesis with in vitro studies, which supports our hypothesis that TIG3 plays an oncogenic role in GBM, though the loss of TIG3 phospholipase A1/A2 activity was showed to promote breast cancer lung metastasis.…”
TIG3 (tazarotene-induced gene 3) has been reported to suppress the progression of several malignancies, where this gene is universally downregulated. However, the expression of TIG3 in primary glioblastoma and its relevance to patient's prognosis have not been elaborated. Thus, this study was aimed to evaluate TIG3 expression level in primary glioblastoma and investigate the prognostic value of TIG3 for patients. The Cancer Genome Atlas database was first utilized to analyze the expression and prognostic potential of TIG3 in 528 glioblastoma cases. Compared with control group, glioblastoma showed significantly elevated TIG3 expression (p < 0.001). Log-rank analysis revealed that higher expression of TIG3 was associated with shorter overall survival (358vs 383 days, p = 0.039). Furthermore, TIG3 protein expression detected by immunohistochemistry confirmed positive correlation of TIG3 expression and glioma grade and upregulation of TIG3 in our cohort of 101 primary glioblastoma patients compared to 16 normal brains. Finally, Kaplan-Meier analysis and Cox regression analysis identified high TIG3 expression as an independent risk factor for overall survival of primary glioblastoma patients (overall survival, 10 vs 13 months, p = 0.033; hazard ratio = 1.542, p = 0.046). Together, this study indicated that increased expression of TIG3 in primary glioblastoma is a novel biomarker for predicting poor outcome of patients. We then hypothesize that TIG3 may function in a different pattern in glioblastoma.
“…in 2015 and showed similar folding to that of HRASLS3, although the basic structure contained four α-helices and a six-stranded antiparallel β-sheet (Fig. 2 ) [ 6 ]. Fig.…”
Section: Introductionmentioning
confidence: 99%
“…Sequence alignment was performed using ClustalW2 [ 51 ] and structural alignment was performed for HRASLS2, HRASLS3, and HRASLS4 as described by Golczak et al in 2012 [ 3 ] and Wei et al . in 2015 [ 6 ]. The β-sheets are indicated by green arrows and α-helices are indicated by red lines Fig 3 Homology domains within the five human HRASLS enzymes.…”
The H-RAS-like suppressor (HRASLS) subfamily consists of five enzymes (1–5) in humans and three (1, 3, and 5) in mice and rats that share sequence homology with lecithin:retinol acyltransferase (LRAT). All HRASLS family members possess in vitro phospholipid metabolizing abilities including phospholipase A1/2 (PLA1/2) activities and O-acyltransferase activities for the remodeling of glycerophospholipid acyl chains, as well as N-acyltransferase activities for the production of N-acylphosphatidylethanolamines. The in vivo biological activities of the HRASLS enzymes have not yet been fully investigated. Research to date indicates involvement of this subfamily in a wide array of biological processes and, as a consequence, these five enzymes have undergone extensive rediscovery and renaming within different fields of research. This review briefly describes the discovery of each of the HRASLS enzymes and their role in cancer, and discusses the biochemical function of each enzyme, as well as the biological role, if known. Gaps in current understanding are highlighted and suggestions for future research directions are discussed.
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