Biology subjects

Morita, E.

Publications and source records attributed to Morita, E..

3 recordsLinked to original sources

bioRxiv2026

Secretion is a second fate for p62 and is coupled to KEAP1/NRF2 signaling

Cells degrade the autophagy receptor p62/sequestosome 1 (SQSTM1) in lysosomes. By knocking the HiBiT peptide into the endogenous SQSTM1 locus, we show that export is a second, quantitatively comparable fate. Specifically, p62 leaves cells continuously inside membrane-enclosed carriers at a rate similar to that of LC3B. Blocking lysosomal degradation amplifies release through an ATG5- and FIP200-dependent route, whereas a basal route persists in autophagy-deficient cells. Thus, p62 exits by at least two parallel pathways. Export requires PB1-mediated self-oligomerization but not LC3 binding, Kelch-like ECH-associated protein 1 (KEAP1) binding, or an intact ubiquitin-associated domain. Hence, oligomerization is the sorting determinant. KEAP1 is also released, and dominant-negative RAB27A retains both proteins inside cells and lowers nuclear factor erythroid 2-related factor 2 transcriptional output. Secretion is therefore a second outlet for the p62-KEAP1 module, and its interruption co-varies with a dampened oxidative stress response.

cell biology↗

bioRxiv2026

Ribonuclease L Regulates Antiviral Responsiveness through Cleavage of XBP1 mRNA

During viral infection, viral replication perturbs endoplasmic reticulum (ER) homeostasis and triggers the unfolded protein response (UPR). XBP1s, a transcription factor generated by one branch of the UPR, is known to potentiate both innate and adaptive immunity, but its role in antiviral responses remains incompletely understood beyond its ability to augment type I interferon (IFN) mRNA induction. Here, we show that XBP1s positively regulates the RIG-I-like receptors (RLRs), ribonuclease L (RNase L), and protein kinase R (PKR) pathways, indicating that it enhances all three major antiviral response pathways. We further show that RNase L activation rapidly decreases XBP1 mRNA levels in an RNase activity-dependent manner, leading to a prompt reduction in XBP1s expression. Consistent with this, RNase L deletion significantly increased both thapsigargin-mediated XBP1s induction and XBP1s expression following Japan encephalitis virus infection. Poly(I:C)-induced IFNB mRNA expression was significantly enhanced in RNase L-knockout cells. This enhancement was completely abolished by RNase L reconstitution. XBP1 knockdown also significantly attenuated IFNB mRNA expression in RNase L-knockout cells. These findings suggest a negative-feedback loop in which RNase L suppresses XBP1s, thereby fine-tuning antiviral responsiveness during viral infection. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/713401v1_ufig1.gif" ALT="Figure 1000"> View larger version (19K): org.highwire.dtl.DTLVardef@112d312org.highwire.dtl.DTLVardef@df79a9org.highwire.dtl.DTLVardef@1ac571borg.highwire.dtl.DTLVardef@18ac610_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Microglia-astrocyte interaction underlies aquaporin-4 dysregulation in the mouse cortex

Brain water homeostasis relies on the coordinated actions of glial cells. In particular, astrocytes play an essential role in facilitating perivascular water exchange between cerebrospinal fluid and interstitial fluid through aquaporin-4 (AQP4), a water channel highly concentrated at astrocytic endfeet. Dysregulation of AQP4 localization is implicated in various neuropathologies, but its underlying mechanisms are unclear. Although astrocytes and microglia both express {beta}-adrenergic receptors ({beta}-AdRs), whether {beta}-AdR signaling modulates astrocytic AQP4 polarization through microglial activation has not yet been investigated. Here, we hypothesized that microglial activation mediates the {beta}-AdR-induced loss of astrocytic AQP4 polarization. To test this hypothesis, we topically applied the {beta}-AdR agonist, isoproterenol, to the primary visual cortex of anesthetized mice and evaluated AQP4 polarization using double immunohistochemistry. Acute {beta}-AdR activation (3 h) significantly reduced perivascular AQP4 polarization and enhanced local microglial reactivity. Both pharmacological inhibition of microglial activity with minocycline and microglial depletion via dietary administration of the CSF1R antagonist, PLX5622, prevented AQP4 dysregulation induced by isoproterenol. These findings demonstrate that microglial activation is required for {beta}-AdR agonist-induced AQP4 dysregulation in the mouse cortex, revealing a previously unrecognized microglia-astrocyte interaction linking adrenergic signaling to glial water homeostasis.

neuroscience↗