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We have demonstrated that the cellular protein M-Sec promotes the transmission of human T-cell leukemia virus type 1 (HTLV-1) in vitro and in vivo. Here, we show how HTLV-1 utilizes M-Sec for its efficient transmission. HTLV-1-infected CD4+ T cells expressed M-Sec at a higher level than uninfected CD4+ T cells. The ex vivo culture of the infected cells upregulated the expression of M-Sec, the level of which was sustained for a long time. The viral structural protein Gag is distributed in a punctate pattern in cells. M-Sec promoted the accumulation of large intracellular Gag puncta. This accumulation was dependent on phosphatidylinositol 4,5-bisphosphate (PIP2), since it was lost upon the removal of PIP2 binding motifs in M-Sec or the depletion of cellular PIP2. The viral envelope protein Env co-localized with the large Gag puncta induced by M-Sec. Furthermore, viral particles produced by M-Sec-expressing cells contained a higher amount of Env. Given that M-Sec alters the cellular distribution of PIP2, these results suggest that M-Sec promotes the formation of infectious viral particles through PIP2. Since the expression of M-Sec is mediated by HTLV-1 Tax protein, M-Sec appears to function in a positive feedback loop that ensures efficient HTLV-1 transmission. Author summary: Human T-cell leukemia virus type 1 (HTLV-1) causes an aggressive blood cancer known as ATL and a neurodegenerative condition known as HAM/TSP. HTLV-1 infects CD4+ T lymphocytes, and induces or upregulates the expression of a wide array of cellular proteins, including M-Sec. Our previous in vitro and in vivo studies have demonstrated that M-Sec mediates an efficient cell-to-cell transmission of HTLV-1. In this study, we discovered that M-Sec can also facilitate virus spread by promoting the formation of infectious viral particles. Mechanistically, our data suggest that through redistribution of phosphatidylinositol 4,5-bisphosphate, M-Sec promotes accumulation of a viral structural protein Gag and an envelope protein Env to large intracellular compartments, and facilitates the incorporation of Env into progeny viral particles. Thus, the current study reveals that M-Sec and its downstream effectors are key host components that govern both the virion infectivity and cell-to-cell transmission and thereby potentially serve as targets of anti-HTLV-1 strategies. [ABSTRACT FROM AUTHOR]

Previous studies indicated that the acquisition of egg fertilizability during transit through the pars recta portion of the oviduct in Bufo japonicus is accompanied by hydrolytic conversion of the vitelline coat 40- to S2-kDa components to 39-kDa components induced by a 66-kDa serine protease, 'oviductin.' In this study, we cloned a 3028-bp cDNA that contained an open reading frame encoding 974 amino acids with a calculated molecular mass of 107.6 kDa, including two protease domains and three repeats of CUB domains. Sequence analysis indicated that the catalytically active 66-kDa protein comprised an N-terminally located oviductin protease and two CUB domains. The oviductin gene was transcribed as a part of 6-kb mRNA that was expressed specifically in the cells lining the bottom of epithelial folds in the oviductal pars recta, and this expression was highly accelerated when the pars recta fragments were cultured in the presence of hCG. Western blot analyses using antibodies against a protease domain revealed that the catalytically inactive 102-kDa proteins in the pars recta granules yield 66-kDa catalytically active and 82- and 59-kDa inactive molecules. We propose that the oviductin translated as 107.6-kDa precursors are processed both N- and C-terminally to give rise to a 66-kDa active form comprising a serine protease and two CUB domains. Key Words: oviductal pars recta; oviductin cDNA; hormonally induced gene expression; posttranslational processing; Bufo japonicus.

The receptor of CSF-1 (CSF1R) encoding tyrosine kinase is essential for tissue macrophage development, and the therapeutic target for many tumors. However, it is not completely understood how CSF1R activation is regulated. Here, we identify the cellular protein TNF-α-induced protein 2 (TNFAIP2) as a unique regulator of CSF1R. CSF1R forms large aggregates in macrophages via unknown mechanisms. The inhibition or knockdown of TNFAIP2 reduced CSF1R aggregate formation and functional response of macrophages to CSF-1, which was consistent with reduced CSF1R activation after CSF-1 stimulation. When expressed in 293 cells, TNFAIP2 augmented CSF1R aggregate formation and CSF-1-induced CSF1R activation. CSF1R and TNFAIP2 bind the cellular phosphatidylinositol 4,5-bisphosphate (PIP2). The removal of the PIP2-binding motif of CSF1R or TNFAIP2, or the depletion of cellular PIP2 reduced CSF1R aggregate formation. Moreover, TNFAIP2 altered the cellular distribution of PIP2. Because CSF-1-induced dimerization of CSF1R is critical for its activation, our findings suggest that TNFAIP2 augments CSF1R aggregate formation via PIP2, which brings CSF1R monomers close to each other and enables the efficient dimerization and activation of CSF1R in response to CSF-1., (© 2025 Abdelnaser et al.)

Cholangiocarcinoma (CCA) is a major cause of cancer deaths in northeast Thailand. It is aggressive, highly metastatic, and responds poorly to traditional chemotherapy. We demonstrated the potential for Cepharanthine (CEP), a biscoclaurine alkaloid extracted from Stephania cepharantha, to treat CCA. CEP significantly inhibited growth of human CCA cell lines in a dose- and time-dependent manner, regardless of the histologic type of tumor origin. Increasing cell apoptosis via caspase-3 and capase-9 activation was demonstrated in CEP-treated cells. We found that CEP controlled the growth of CCA cells through nuclear factor-kappa B (NF-kappaB) inactivation by inhibiting nuclear translocation. CEP treatment effectively reduced tumor size in CCA-inoculated mice without serious side effects. CEP also increased cell apoptosis in primary histocultures of CCA patients' tissues; this was demonstrated by immunohistochemistry using TUNEL staining. Our results suggest that CEP possesses therapeutic potential against human CCA.