USP8 prevents aberrant NF-κB and Nrf2 activation by counteracting ubiquitin signals from endosomes

K63-linked ubiquitin chains attached to plasma membrane proteins serve as tags for endocytosis and endosome-to-lysosome sorting. USP8 is an essential deubiquitinase for the maintenance of endosomal functions. Prolonged depletion of USP8 leads to cell death, but the major effects on cellular signaling pathways are poorly understood. Here, we show that USP8 depletion causes aberrant accumulation of K63-linked ubiquitin chains on endosomes and induces immune and stress responses. Upon USP8 depletion, two different decoders for K63-linked ubiquitin chains, TAB2/3 and p62, were recruited to endosomes and activated the TAK1-NF-κB and Keap1-Nrf2 pathways, respectively. Oxidative stress, an environmental stimulus that potentially suppresses USP8 activity, induced accumulation of K63-linked ubiquitin chains on endosomes, recruitment of TAB2, and expression of the inflammatory cytokine. The results demonstrate that USP8 is a gatekeeper of misdirected ubiquitin signals and inhibits immune and stress response pathways by removing K63-linked ubiquitin chains from endosomes.</p

A de novo dominant-negative variant is associated with OTULIN-related autoinflammatory syndrome

稀少遺伝性自己炎症性疾患: OTULIN関連自己炎症症候群の新たな病態を解明～既報の疾患に新たな視点を追加し、未診断患者の診断や炎症・細胞死研究の進展に期待～. 京都大学プレスリリース. 2024-04-25.OTULIN-related autoinflammatory syndrome (ORAS), a severe autoinflammatory disease, is caused by biallelic pathogenic variants of OTULIN, a linear ubiquitin-specific deubiquitinating enzyme. Loss of OTULIN attenuates linear ubiquitination by inhibiting the linear ubiquitin chain assembly complex (LUBAC). Here, we report a patient who harbors two rare heterozygous variants of OTULIN (p.P152L and p.R306Q). We demonstrated accumulation of linear ubiquitin chains upon TNF stimulation and augmented TNF-induced cell death in mesenchymal stem cells differentiated from patient-derived iPS cells, which confirms that the patient has ORAS. However, although the de novo p.R306Q variant exhibits attenuated deubiquitination activity without reducing the amount of OTULIN, the deubiquitination activity of the p.P152L variant inherited from the mother was equivalent to that of the wild-type. Patient-derived MSCs in which the p.P152L variant was replaced with wild-type also exhibited augmented TNF-induced cell death and accumulation of linear chains. The finding that ORAS can be caused by a dominant-negative p.R306Q variant of OTULIN furthers our understanding of disease pathogenesis

Critical current density and vortex dynamics in pristine and proton-irradiated Ba0.6K0.4Fe2As2

The screening current density (J) and vortex pinning properties for H| | c are studied in optimally hole-doped Ba0.6K0.4Fe2As2 single crystals with a superconducting transition of Tc = 38.6 K. We utilize the irreversible magnetization and its relaxation to evaluate the screening current density and vortex dynamics before and after the introduction of point defects created by 3-MeV proton (H+) irradiation with a dose of 5.8×10 16H+cm2. In the as-grown crystal, both J and vortex dynamics are strongly influenced by temperature and magnetic field, indicating that the predominant pinning is not the weak-collective pinning but the strong pinning. With an introduction of point defects, J in the H+-irradiated crystal at 2 K reaches 1.1×10 7 cm−2, which is one of the largest values in iron-based superconductors. In contrast to the as-grown sample, the sensitivity to the temperature and magnetic field becomes quite mild, and the vortex system is described by a simple weak-collective pinning scenario

Pair-breaking effects induced by 3-MeV proton irradiation in Ba1−xKxFe2As2

Pair-breaking effects induced by 3-MeV proton irradiations are examined in underdoped, optimally doped, and overdoped Ba 1−x K x Fe 2 As 2 single crystals in terms of suppression of the superconducting critical temperature T c . The small residual resistivity (RR) in as-grown crystals shows the presence of negligible intrinsic scatterings, which makes this material a model system for studying the effect of artificially introduced scatterings. The RR and T c change linearly with the proton dose. As in the case of proton irradiation in Co-doped BaFe 2 As 2 , we do not detect any low-temperature upturns in resistivity attributable to magnetic scattering or localization. Regardless of K doping levels, the critical value of the normalized scattering rate is much higher than that expected in s ± -wave superconductors