Biology subjects

Oikawa, D.

Publications and source records attributed to Oikawa, D..

4 recordsLinked to original sources

bioRxiv2025

LRBA promotes drug-induced liver injury and MASLD by scaffolding MAPK activation

LPS-responsive beige-like anchor protein (LRBA) regulates vesicular trafficking and receptor recycling, and its deficiency results in immunodeficiency characterized by hypogammaglobulinemia and autoimmune syndrome. However, its role in liver pathophysiology remains unclear. Here, we reveal a previously unrecognized function of LRBA as a critical intracellular scaffold for mitogen-activated protein kinase (MAPK) activation that promotes liver injury. Lrba-/-mice exhibit reduced acetaminophen (APAP)-induced hepatic necrosis through the suppression of JNK activation. In a model of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by a high-fat, high-cholesterol (HFHC) diet, Lrba deficiency reduces hepatic inflammation, fibrosis, and Kupffer cell activation. Mechanistically, LRBA homodimers directly interact with specific mitogen-activated protein kinase kinase kinases (MAP3Ks), including transforming growth factor-{beta}-activated kinase 1 (TAK1) and mixed-lineage kinase 3 (MLK3), to facilitate their activation. LRBA, which is primarily expressed in hepatocytes under physiological conditions, is upregulated in non-parenchymal cells such as Kupffer cells and cholangiocytes in both HFHC diet-fed mice and patients with MASLD and cirrhosis, linking its scaffolding function to pathological inflammation. Thus, LRBA promotes liver disease progression by amplifying inflammatory signaling.

cell biology↗

bioRxiv2025

A single-cell fixed RNA profiling of liver fibrosis progression and regression reveals SEMA4D and LMCD1 as key mediators of fibrogenesis

Liver fibrosis progression and regression are dynamic processes involving diverse hepatic and immune cell populations. Here, we utilize single-cell fixed RNA profiling (FLEX) of a TAA-induced mouse liver cirrhosis model, with and without a recovery phase, to depict the cellular landscape and molecular mechanisms of fibrosis resolution. The regression phase was characterized by the emergence of pericentral hepatocytes enriched in detoxification and antioxidant genes (e.g., Cyp2e1, Txn1), which secreted Rarres2 to modulate hepatic stellate cell (HSC) function. This was accompanied by the upregulation of scar-resolving genes (Mmp14, Ctsl), restoration of fenestrae in liver sinusoidal endothelial cells, anti-inflammatory phenotypes of Kupffer cells, a decrease in fibrogenic cholangiocyte subsets, and recovery-associated signatures in NK/T cells, B cells, and neutrophils. In contrast, SEMA4D secreted by monocyte-derived macrophages during fibrosis progression activated Plxnb2 HSCs, and its blockade attenuated fibrosis in vivo. Furthermore, LMCD1 was identified as a novel marker for HSC activation and regulation. This single-cell atlas reveals key transcriptional programs and intercellular signaling pathways dependent on the fibrotic condition, offering new therapeutic targets for liver cirrhosis.

cell biology↗

bioRxiv2023

Optineurin deficiency impairs autophagy to cause interferon beta overproduction and increased survival of mice following viral infection

BackgroundOptineurin (OPTN) is associated with several human diseases, including amyotrophic lateral sclerosis (ALS), and is involved in various cellular processes, including autophagy. Optineurin regulates the expression of interferon beta (IFN{beta}), which plays a central role in the innate immune response to viral infection. However, the role of optineurin in response to viral infection has not been fully clarified. It is known that optineurin-deficient cells produce more IFN{beta} than wild-type cells following viral infection. In this study, we investigate the reasons for, and effects of, IFN{beta} overproduction during optineurin deficiency both in vitro and in vivo. MethodsTo investigate the mechanism of IFN{beta} overproduction, viral nucleic acids in infected cells were quantified by RT-qPCR and the autophagic activity of optineurin-deficient cells was determined to understand the basis for the intracellular accumulation of viral nucleic acids. Moreover, lethal viral infection experiments using optineurin-disrupted (Optn-KO) animals were performed. ResultsIFN{beta} overproduction following viral infection was observed not only in several types of optineurin-deficient cell lines but also in Optn-KO mice and human ALS patient cells carrying mutations in OPTN. IFN{beta} overproduction in Optn-KO cells was revealed to be caused by excessive accumulation of viral nucleic acids, which was a consequence of reduced autophagic activity caused by the loss of optineurin. Additionally, IFN{beta} overproduction in Optn-KO mice suppressed viral proliferation, resulting in increased mouse survival following lethal viral challenge. ConclusionOur findings indicate that the combination of optineurin deficiency and viral infection leads to IFN{beta} overproduction in vitro and in vivo. The effects of optineurin deficiency are elicited by viral infection, therefore, viral infection may be implicated in the development of optineurin-related diseases.

immunology↗

bioRxiv2021

OTUD1 deubiquitylase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways

Deubiquitylating enzymes (DUBs) regulate numerous cellular functions by removing ubiquitin modifications. We examined the effects of 88 human DUBs on linear ubiquitin chain assembly complex (LUBAC)-induced NF-{kappa}B activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-{kappa}B pathway by hydrolysing K63-linked ubiquitin chains from NF-{kappa}B signalling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-{kappa}B activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. The N-terminal intrinsically disordered region of OTUD1, which contains an EGTE motif, is indispensable for KEAP1-binding and NF-{kappa}B suppression. OTUD1 is involved in the KEAP1-mediated antioxidant response and reactive oxygen species (ROS)-induced cell death, oxeiptosis. In Otud1-/--mice, inflammation, oxidative damage, and cell death were enhanced in inflammatory bowel disease, acute hepatitis, and sepsis models. Thus, OTUD1 is a crucial regulator for the inflammatory, innate immune, and oxidative stress responses and ROS-associated cell death pathways.

cell biology↗