Biology subjects

Hiyoshi, M.

Publications and source records attributed to Hiyoshi, M..

3 recordsLinked to original sources

bioRxiv2026

Mouse suppressyn-like 1 is an endogenous retrovirus-derived inhibitor of membrane fusion through direct association with envelope glycoproteins

Cell-cell fusion is essential for placental development and is mediated by endogenous retrovirus (ERV)-derived fusogens known as syncytins. However, how ERV-derived proteins negatively regulate membrane fusion remains largely unknown. Here, we identify a previously uncharacterized murine ERV envelope-derived protein, mouse suppressyn-like 1 (mSUPYNL1), that suppresses syncytin-mediated membrane fusion through a mechanism distinct from that of placental human suppressyn (hSUPYN). Unlike hSUPYN, which acts through receptor interference, mSUPYNL1 inhibits both murine and human syncytin-mediated fusion independently of receptor usage by associating with the surface (SU) subunits of multiple syncytin envelope glycoproteins, revealing a receptor-independent mechanism of fusion suppression. This mechanism extends beyond endogenous fusogens. mSUPYNL1 also associates with the SU glycoprotein (gp46) of Human T-cell Leukemia Virus type 1 (HTLV-1) and suppresses Env-dependent syncytium formation, whereas hSUPYN showed no detectable antiviral activity in this assay. These findings identify mSUPYNL1 as a broad-spectrum inhibitor of envelope glycoprotein-mediated membrane fusion. Analysis of mSUPYNL1 knockout mice revealed that, in contrast to the placenta-restricted expression of hSUPYN, mSUPYNL1 was broadly expressed, with its most prominent localization in decidual stromal and vascular endothelial cells of the pregnant uterus, as well as in hematopoietic tissues such as the spleen and thymus. Together, our findings uncover an evolutionarily distinct class of ERV-derived fusion suppressors that function through envelope glycoprotein recognition instead of receptor interference. Our study expands current models of ERV domestication by demonstrating that retroviral envelope proteins have been independently co-opted not only to promote membrane fusion but also to restrain it, thereby linking placental biology, antiviral defense, and host evolution. HIGHLIGHTSO_LImSUPYNL1 is an endogenous retrovirus-derived membrane fusion inhibitor C_LIO_LImSUPYNL1 binds the SU domains of murine and human syncytins C_LIO_LImSUPYNL1 suppresses HTLV-1 Env-mediated syncytium formation C_LIO_LIDirect envelope recognition enables receptor-independent fusion inhibition C_LI

developmental biology↗

bioRxiv2025

M-Sec promotes the production of infectious HIV-1 virus through the exocyst complex

We have demonstrated that the cellular protein M-Sec promotes the transmission of human immunodeficiency virus type 1 (HIV-1). However, the underlying mechanism is not fully understood. Here, we report that M-Sec promotes the production of infectious HIV-1 virus. The major viral structural protein Gag distributed as many puncta in infected cells, which is one of the indicators of viral particle formation. The knockdown of M-Sec hindered the Gag puncta formation and co-localization of Gag with the viral envelope protein Env in cells, and reduced the amount of Env and infectivity of the produced virus. Consistent with these results, the over-expression of M-Sec induced the accumulation of Gag puncta, Gag/Env co-localization, and Env incorporation into virus and viral infectivity. M-Sec is known to bind phosphatidylinositol 4,5-bisphosphate (PIP2) and a small GTPase Ral, both of which were required for the M-Sec-mediated HIV-1 regulation. The exocyst complex, which is the downstream effector of Ral, was also required for the M-Sec-mediated HIV-1 regulation. Because PIP2, Ral and the exocyst complex are important for the M-Sec-mediated formation of the long plasma membrane protrusions, the present study suggests that M-Sec promotes HIV-1 transmission by acting on both cell structures and viral production through these overlapping components. Author SummaryDespite an effective anti-retroviral therapy, human immunodeficiency virus type 1 (HIV-1) persists in a fraction of infected cells, which is an obstacle to cure. HIV-1 exploits the cell-to-cell infection for its transmission, which is more efficient than infection by cell-free virus. Thus, it is important to fully understand the process of cell-to-cell infection towards the HIV-1 cure. We previously identified M-Sec as the cellular protein that potentiates the cell-to-cell infection of HIV-1. However, the underlying mechanism is not fully explained. In this study, we discovered that M-Sec promotes the production of infectious HIV-1 particles. Mechanistically, M-Sec affects the intracellular dynamics of the major viral structural protein Gag, which leads to an efficient incorporation of the viral envelope protein Env into viral particles. This activity of M-Sec depends on PIP2 (the phosphoinositide), Ral (the small GTPase), and the exocyst complex (the downstream effector of Ral), all of which are involved in vesicular trafficking. Thus, the present study identifies M-Sec and related molecular components as potential targets of anti-HIV-1 strategies.

microbiology↗

bioRxiv2024

Identification of M-Sec as a unique cellular regulator of CSF-1 receptor activation

Fms, the CSF-1 receptor encoding tyrosine kinase, is essential for tissue macrophage development, and the therapeutic target for many tumors. However, it is not completely understood how Fms activation is regulated. Here, we identify the cellular protein M-Sec as a unique regulator of Fms. In macrophages, Fms forms large aggregates via unknown mechanisms. We found that the inhibition or knockdown of reduced Fms aggregate formation and functional response of macrophages to CSF-1, which was consistent with reduced Fms activation after CSF-1 stimulation. When expressed in 293 cells, M-Sec augmented Fms aggregate formation and CSF-1-induced Fms activation. CSF-1 and M-Sec bind the cellular phosphatidylinositol 4,5-biphosphate (PIP2). The removal of PIP2-binding motif of Fms or M-Sec, or the depletion of cellular PIP2 reduced Fms aggregate formation. Moreover, M-Sec altered cellular distribution of PIP2. Since CSF-1-induced dimerization of Fms is critical for its activation, our findings suggest that M-Sec augments large Fms aggregate formation via PIP2, which brings Fms monomers close to each other and enables the efficient dimerization and activation of Fms in response to CSF-1.

molecular biology↗