The Role Played by Transcription Factor E3 in Modulating Cardiac Hypertrophy.

Transcription factor E3 (TFE3), which is a key regulator of cellular adaptation, is expressed in most tissues, including the heart, and is reportedly overexpressed during cardiac hypertrophy. In this study, TFE3's role in cardiac hypertrophy was investigated. To understand TFE3's physiological importance in cardiac hypertrophy, pressure-overload cardiac hypertrophy was induced through transverse aortic constriction (TAC) in both wild-type (WT) and TFE3 knockout mice (TFE3-/-). Eleven weeks after TAC induction, cardiac hypertrophy was observed in both WT and TFE3-/- mice. However, significant reductions in ejection fraction and fractional shortening were observed in WT mice compared to TFE3-/- mice. To understand the mechanism, we found that myosin heavy chain (Myh7), which increases during hemodynamic overload, was lower in TFE3-/- TAC mice than in WT TAC mice, whereas extracellular signal-regulated protein kinases (ERK) phosphorylation, which confers cardioprotection, was lower in the left ventricles of WT mice than in TFE3-/- mice. We also found high expressions of TFE3, histone, and MYH7 and low expression of pERK in the normal human heart compared to the hypertensive heart. In the H9c2 cell line, we found that ERK inhibition caused TFE3 nuclear localization. In addition, we found that MYH7 was associated with TFE3, and during TFE3 knockdown, MYH7 and histone were downregulated. Therefore, we showed that TFE3 expression was increased in the mouse model of cardiac hypertrophy and tissues from human hypertensive hearts, whereas pERK was decreased reversibly, which suggested that TFE3 is involved in cardiac hypertrophy through TFE3-histone-MYH7-pERK signaling.

Fusobacterium nucleatum subsp. nucleatum RadD binds Siglec-7 and inhibits NK cell-mediated cancer cell killing.

Fusobacterium nucleatum is an oral commensal bacterium that can colonize extraoral tumor entities, such as colorectal cancer and breast cancer. Recent studies revealed its ability to modulate the immune response in the tumor microenvironment (TME), promoting cancer progression and metastasis. Importantly, F. nucleatum subsp. animalis was shown to bind to Siglec-7 via lipopolysaccharides, leading to a pro-inflammatory profile in human monocyte-derived dendritic cells. In this study, we show that F. nucleatum subsp. nucleatum RadD binds to Siglec-7 on NK cells, thereby inhibiting NK cell-mediated cancer cell killing. We demonstrate that this binding is dependent on arginine residue R124 in Siglec-7. Finally, we determine that this binding is independent of the known interaction of RadD with IgA. Taken together, our findings elucidate the targeting of Siglec-7 by F. nucleatum subsp. nucleatum RadD as a means to modulate the NK cell response and potentially promoting immune evasion and tumor progression.

Studying TIGIT activity against tumors through the generation of knockout mice.

The use of antibodies to block inhibitory receptors, primarily anti-PD1 and CTLA4 (known as checkpoint therapy) revolutionized cancer treatment. However, despite these successes, the majority of cancer patients do not respond to the checkpoint treatment, emphasizing the need for development of additional therapies, which are based on other inhibitory receptors. Human TIGIT is an inhibitory receptor expressed by Natural Killer (NK) and T cells and is mainly known to interact with PVR, Nectin-2, Nectin-3, and Nectin-4. Whether mouse TIGIT interacts with all of these ligands is still unclear. Additionally, the in vivo function of TIGIT against tumors is not completely understood. Here, we demonstrate that mouse TIGIT interacts with and is inhibited by mPVR only. Using CRISPR-Cas9 technology, we generated TIGIT-deficient mice and demonstrated that NK cell cytotoxicity and degranulation against two tumor types were lower in WT mice when compared to the TIGIT KO mice. Moreover, in vivo tumor progression was slower in TIGIT KO than in WT mice. Taken together, our data established that mTIGIT has only one ligand, PVR, and that in the absence of TIGIT tumors are killed better both in vitro and in vivo.

CLPTM1L is a GPI-anchoring pathway component targeted by HCMV.

The GPI-anchoring pathway plays important roles in normal development and immune modulation. MHC Class I Polypeptide-related Sequence A (MICA) is a stress-induced ligand, downregulated by human cytomegalovirus (HCMV) to escape immune recognition. Its most prevalent allele, MICA*008, is GPI-anchored via an uncharacterized pathway. Here, we identify cleft lip and palate transmembrane protein 1-like protein (CLPTM1L) as a GPI-anchoring pathway component and show that during infection, the HCMV protein US9 downregulates MICA*008 via CLPTM1L. We show that the expression of some GPI-anchored proteins (CD109, CD59, and MELTF)-but not others (ULBP2, ULBP3)-is CLPTM1L-dependent, and further show that like MICA*008, MELTF is downregulated by US9 via CLPTM1L during infection. Mechanistically, we suggest that CLPTM1L's function depends on its interaction with a free form of PIG-T, normally a part of the GPI transamidase complex. We suggest that US9 inhibits this interaction and thereby downregulates the expression of CLPTM1L-dependent proteins. Altogether, we report on a new GPI-anchoring pathway component that is targeted by HCMV.