Tanc1/2 TPR domain interacts with Myo18a C-terminus and undergoes liquid-liquid phase separation.

Tanc1 and its homologous protein Tanc2 are critical synaptic scaffold proteins which regulate synaptic spine densities and excitatory synapse strength. Recent studies indicated TANC1 and TANC2 are candidate genes of several neurodevelopmental disorders (NDDs). In this study, we identified and characterized a novel interaction between Tanc1/2 and Myo18a, mediated by the Tanc1/2 TPR domains and Myo18a coiled-coil domain and C-extension (CCex). Sequence analysis and size exclusion chromatography experiments reveal that high salt disrupts the interaction between Myo18a and Tanc1/2, indicating that the interaction is primarily driven by charge-charge interactions. More importantly, we found that the Tanc1-TPR/Myo18a CCex interaction could undergo liquid-liquid phase separation (LLPS) in both cultured cells and test tubes, which provides the biochemical basis and potential molecular mechanisms for the LLPS-mediated interactions between Myo18a and Tanc1/2.

Induction of lysosomal exocytosis and biogenesis via TRPML1 activation for the treatment of uranium-induced nephrotoxicity.

Uranium (U) is a well-known nephrotoxicant which forms precipitates in the lysosomes of renal proximal tubular epithelial cells (PTECs) after U-exposure at a cytotoxic dose. However, the roles of lysosomes in U decorporation and detoxification remain to be elucidated. Mucolipin transient receptor potential channel 1 (TRPML1) is a major lysosomal Ca2+ channel regulating lysosomal exocytosis. We herein demonstrate that the delayed administration of the specific TRPML1 agonist ML-SA1 significantly decreases U accumulation in the kidney, mitigates renal proximal tubular injury, increases apical exocytosis of lysosomes and reduces lysosomal membrane permeabilization (LMP) in renal PTECs of male mice with single-dose U poisoning or multiple-dose U exposure. Mechanistic studies reveal that ML-SA1 stimulates intracellular U removal and reduces U-induced LMP and cell death through activating the positive TRPML1-TFEB feedback loop and consequent lysosomal exocytosis and biogenesis in U-loaded PTECs in vitro. Together, our studies demonstrate that TRPML1 activation is an attractive therapeutic strategy for the treatment of U-induced nephrotoxicity.

In-situ growth of gold nanoparticles on a 3D-network consisting of a MoS2/rGO nanocomposite for simultaneous voltammetric determination of ascorbic acid, dopamine and uric acid.

A glassy carbon electrode was modified with a 3D-networked nanostructure composed of MoS2, reduced graphene oxide and gold nanoparticles (3D-MoS2/rGO/Au). The composites were prepared through in-situ growth of gold nanoparticles on 3D-MoS2/rGO nanosheets via a hydrothermal method. The morphology and electrochemical features of the composite were investigated. The 3D-MoS2/rGO/Au sensor exhibits excellent electrocatalytic activity for simultaneous detection of ascorbic acid (AA), dopamine (DA) and uric acid (UA). The oxidation potentials are well separated at around -0.05 V for AA, 0.06 V for DA and 0.2 V for UA, respectively. The detection limits for individual detection and simultaneous detection (S/N = 3) are 0.93 µM and 1.46 µM for AA, 0.11 µM and 0.15 µM for DA, and 0.74 µM and 0.29 µM for UA. The method was applied to the quantitative analysis of AA, DA, and UA in spiked serum samples with satisfying results. Graphical abstract In-situ growth of gold nanoparticles on 3D-networked MoS2/rGO nanocomposite for individual and simultaneous determination of ascorbic acid, dopamine and uric acid.