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Gene & Protein in Disease The roles and mechanisms of ETS1 in diseases

transcription factor family, the ETS1 protein not only of exon VII . The loss of the inhibitory domain in the exon
[8]
is highly conserved in its ETS domain but also exhibits VII domain causes the elimination of the autoinhibitory
extensive conservation throughout its entire protein module in DeltaVII-ETS1, which in turn unleashes the
sequence, indicating that the amino acid sequence of ETS1 complete DNA binding activity of ETS1 . Afterward,
[9]
as a whole is essentially under evolutionary pressure and the ETS1 protein can perform better DNA binding,
that each component may be crucial for the growth and achieving gene expression and transcriptional activity
differentiation of metazoans. superior to those of the fl-ETS1 protein. However, the

Due to the high conservation and high expression of balance in differential regulation between DeltaVII-ETS1
ETS1 in immune tissues, the mechanisms and its effects on and fl-ETS1 suggests a possible mechanism that governs
[8]
the occurrence of immune-related diseases have attracted lymphoid maturation and homeostasis . The ETS domain
increasing attention. An in-depth study showed that the possesses a winged helix turn helix (wHTH) structure with
ETS1 protein plays pivotal roles in stem cell development, three α-helices and four β-sheets that exclusively identify
[10]
cell aging, and death, as well as tumor progression by acting and attach to a core purine-rich 5ʹ-GGAA/T-3′ motif .
as a transcriptional activator or inhibitor of several genes . The recognition mechanism of ETS1 through homologous
[2]
[11]
The roles of ETS1 are also tightly connected to immune- sequences in the ETS domain has also been described .
related diseases . This paper reviews the structure and The autoinhibitory module consists of two inhibitory
[5]
function of ETS1 as well as its roles and mechanisms in the domains adjacent to the ETS domain, which prevents ETS1
occurrence of immune-related diseases. from binding to DNA. Two inhibitory domains constitute
four α-spiral structures: the HI-1 and HI-2 helices are
2. Structure and function of ETS1 located in the N-terminal region, while the H4 and H5
helices are in the C-terminal region [12,13] . These helices
The ETS1 protein is a nuclear protein, with a size of form a spiral bundle that interacts with the ETS domain,
54 kDa that mainly functions as a transcription activator, thus inhibiting the binding of the ETS domain to DNA .
[14]
but other studies have shown that it can also inhibit gene
transcription . The human ETS1 protein is composed 3. Effect and mechanism of action of ETS1
[6]
of 441 amino acids, which are composed of a pointed in the occurrence of autoimmune diseases
domain (54 – 134 aa), a transactivation domain (TAD;
135 – 242 aa), an exon VII domain (242 – 331 aa), an ETS 3.1. Systemic lupus erythematosus (SLE)
domain (331 – 415 aa), and an autoinhibitory module SLE is an autoimmune disease that interferes with the
(two separated sequences, one in the exon VII domain immune response, damaging multiple organs serving
between 301 aa and 330 aa and the other at the C-terminal the host immune system. Two previous genome-wide
end between 416 and 441 aa) (Figure 1). These structural association studies conducted in Han Chinese and
domains are adjacent to each other on the chromosome Asian populations have shown that susceptibility to SLE
and play different regulatory roles. is correlated with ETS1 gene mutations [15,16] . A recent
The pointed domain, a sterile alpha motif domain, research, which utilized single-cell RNA sequencing to
serves as a platform for protein-protein interactions. In analyze peripheral blood mononuclear cells of multiple
addition, extracellular regulated protein kinase 2 (ERK2) SLE age groups, has shown that ETS1 is a susceptibility
can partially bind to this region and phosphorylate ETS1 gene associated with SLE . These results all indicate a
[17]
at Thr38 and Ser41 . The exon VII domain contains an close relationship between ETS1 and SLE. Moreover, a
[7]
inhibitory domain that is an autoinhibitory unit. Full-length study has shown that ETS1 is a critical negative regulatory
ETS1 (fl-ETS1) and DeltaVII-ETS1 are the two naturally factor in Th17 cells . Recently, investigations focusing on
[18]
occurring protein isoforms produced by alternative splicing whether the negative regulatory effect of ETS1 on B cells

Figure 1. Schematic structure of the ETS1 protein. The schematic shows the positions of the different domains within the fl-ETS1 and DeltaVII-ETS1
proteins. The two inhibitory domains (IDs) flanking the ETS-DBD (DNA binding domain) form an autoinhibitory module that controls ETS1 DNA
binding activity. DeltaVII-ETS1 lacks part of the inhibitory module and forms more stable complexes with DNA.

Volume 2 Issue 4 (2023) 2 https://doi.org/10.36922/gpd.2141