SMYD2
Most of the data concerning the relationship between SMYD2 and the
immune system refer to its methyltransferase activity on histone 3
lysine 36 (H3K36) (Brown et al. 2006). Nonetheless, SMYD2 enzymatic
activity is not restricted to H3K36, and this enzyme can also act on
histone 4 lysine 20 (H4K20), among other targets (Boehm et al. 2017; Yi,
Jiang, and Fang 2019).
With reference to haematopoiesis, Velinder et al. showed that
SMYD2 methylates growth factor independent 1 transcription repressor
(GFI1), which is a master regulator of normal and malignant
haematopoiesis. The proposed mechanism was that this specific
methylation in GFI1 protein provokes recruitment of lysine demethylase
1A (LSD1) and repression of the transcription of GFI1-targeted genes,
leading to normal and/or malignant haematopoiesis (Velinder et al.
2016).
In addition, SMYD2 plays a role in macrophages. Xu et al.identified SMYD2 as a negative regulator of macrophage activation and M1
polarization. Smyd2 upregulation abrogated macrophage production
of IL-6 and TNFα, among other proinflammatory cytokines, by catalysing
H3K36 dimethylation on Tnf and Il6 promoters and
suppression of nuclear factor kappa B subunit 1 (NFκB) and extracellular
signal-regulated kinase (ERK) signalling (Xu et al. 2015). Li et
al. studied macrophages in pathological conditions, such as exposure to
the plastics industry widely-used chemicals bisphenol A and phthalate.
These chemicals affect peritoneal macrophages by hampering their
capacity to produce proinflammatory cytokines, express scavenger
receptors and phagocytise. SMYD2 seemed to be involved in this process
since SMYD2 knockdown or inhibition of its methyltransferase activity
led to an expected decrease in H3K36 dimethylation and activation of
IL-6 and TNFα expression, although the phagocytic capacity of the
macrophages was unexpectedly reduced (Li et al. 2018).
Immune cells are directly involved in inflammatory disorders such as
rheumatoid arthritis. The TNFα inhibitor etanercept (commonly used for
the treatment of rheumatoid arthritis) diminished the protein levels of
SMYD2 and also H3K36 trimethylation in the C-C motif chemokine ligand 2
(CCL2) promoter region in a lipopolysaccharide (LPS)-stimulated
human monocytic cell line. These and other data presented by the authors
indicate that the mechanism of action of this drug involves suppression
of LPS-induced CCL2 expression by inhibiting SMYD2 and other
methyltransferases (Y. C. Lin et al. 2017).
With respect to immune system-related malignancies, high expression
levels of SMYD2 were described in many types of leukaemia by Brownet al . In B-cell acute lymphoblastic leukaemia there was a
positive correlation between high SMYD2 and low overall patient
survival. Haematopoietic stem cell-specific SMYD2 KO mice displayed
aberrant haematopoiesis caused by apoptosis induction and changes in
gene expression. Indeed, SMYD2 controls gene expression programmes
related to wingless-related integration site (WNT) regulation of
haematopoietic stem cells proliferation, in part by its association with
Frizzled Receptor 2 (FZD2) (Brown et al. 2020). Another study confirmed
the previous results (Brown et al. 2020); SMYD2 was overexpressed
in acute lymphoblastic leukaemia compared to non-malignant bone marrow
and high SMYD2 expression negatively correlated with overall
survival in acute lymphoblastic leukaemia. A decrease in SMYD2expression was observed 29 days after chemotherapy in most of the
patients who responded to the treatment (leukaemia remission was
determined by the presence of less than 5% of leukaemic cells in bone
marrow) (Sakamoto et al. 2014). Similar results were obtained by Zhanget al. who observed overexpression of SMYD2 in the bone
marrow of children with B lineage acute lymphoblastic leukaemia, which
was associated with bad prognosis (including increased white blood cell
count and less overall survival and tumour-free survival) and a
reduction of SMYD2 expression levels after remission (Zhang et al.
2020). Animal studies demonstrated that, although germ-line SMYD2 KO
mice are viable, healthy and display normal haematopoiesis, SMYD2
deficiency delayed and reduced penetrance of death due to
MLL-AF9/NRasG12D-induced acute myeloid leukaemia.
After disease establishment, both wild-type (WT) and SMYD2 KO cells gave
rise to indistinguishable acute myeloid leukaemia phenotypes, but SMYD2
deletion caused competitive disadvantages over their WT counterpartsin vitro and in vivo . The authors also described direct
binding of Myc to Smyd2 promoter as a possible molecular
mechanism for this phenotype (Bagislar et al. 2016). Moreover,
Oliveira-Santos et al. found that both SMYD2 andSMYD3 were upregulated in malignant B cells from the same
patients with chronic lymphocytic leukaemia, indicating that these two
SMYD proteins may be controlled by the same molecular mechanism in this
biological context. Interestingly, patients with very low expression ofSMYD2 and SMYD3 displayed elevated white blood cell counts
and a complex karyotype (Oliveira-Santos et al. 2016). Furthermore, Hayet al. noticed that premalignant thymus from RUNX family
transcription factor 2 (RUNX2) / myelocytomatosis oncogene (MYC)
transgenic mice overexpress Smyd2 and, by extrapolating data from
murine primary fibroblasts, they speculated that SMYD2 (but not SMYD5)
may inhibit the senescence-like growth arrest caused by RUNX
upregulation in RUNX2/MYC lymphoma, thereby acting as an oncogene (Hay
et al. 2019). Indeed, altogether, these data indicate that SMYD2 has an
oncogenic role in leukaemia.
On the contrary, Zipin-Roitman et al. observed that low
expression of SMYD2 in acute myeloid leukaemia patients negatively
correlated with treatment response and the probability of tumour-free
survival. In addition, human acute myeloid leukaemia cells devoid of
SMYD2 were more resistant to DNA damage caused by irradiation compared
to control cells, and the mechanism leading to this resistance seemed to
be the induction of transient quiescence. The decrease in SMYD2 levels
led to a compensatory increase of SET domain-containing protein (SET)7/9
methyltransferase levels, suggesting an interplay between the two
enzymes that induces quiescence of leukaemia cells, which then become
more resistant to chemotherapy (DNA damage) (Zipin-Roitman et al. 2017).
In addition to macrophages and blood malignancies, SMYD2 is also
implicated in host-pathogen interactions. Infection withLeishmania donovani , the intracellular parasite responsible for
leishmaniasis, activated the expression of Smyd2 via c-Mycin murine cell lines and primary macrophages. This parasitic infection
also caused H3K36 dimethylation at the TNFα promoter, probably by the
enzymatic action of SMYD2. Pharmacological inhibition of SMYD2 using
AZ505 enhanced the protective inflammatory response in infected
macrophage cell lines and decreased parasite multiplication in infected
mice. Thus, SMYD2, along with other methyltransferases, aidsLeishmania donovani in the process of infecting the host (Parmar,
Chandrakar, and Kar 2020). Moreover, using human CD4+ cells lines and T
cells from human immunodeficiency virus type 1 (HIV-1)-infected donors,
Boehm et al. demonstrated that SMYD2 mediates H4K20
monomethylation in the HIV-1 promoter located in the 5’ long terminal
repeat. H4K20 monomethylation promotes association of the reader protein
L3MBTL histone methyl-lysine binding protein 1 (L3MBTL1) with the 5’
long terminal repeat. The presence of SMYD2 is required for this
association and necessary for HIV latency, since SYMD2 knockdown or
inhibition reactivates the virus. Thus, SMYD2 positively regulates HIV-1
latency (Boehm et al. 2017).