Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-κB Activation

Activation of nuclear factor-κB (NF-κB), a key mediator of inducible transcription in immunity, requires binding of NF-κB essential modulator (NEMO) to ubiquitinated substrates. Here, we report that the UBAN (ubiquitin binding in ABIN and NEMO) motif of NEMO selectively binds linear (head-to-tail) ubiquitin chains. Crystal structures of the UBAN motif revealed a parallel coiled-coil dimer that formed a heterotetrameric complex with two linear diubiquitin molecules. The UBAN dimer contacted all four ubiquitin moieties, and the integrity of each binding site was required for efficient NF-κB activation. Binding occurred via a surface on the proximal ubiquitin moiety and the canonical Ile44 surface on the distal one, thereby providing specificity for linear chain recognition. Residues of NEMO involved in binding linear ubiquitin chains are required for NF-κB activation by TNF-α and other agonists, providing an explanation for the detrimental effect of NEMO mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency

Sedentary Time and All-Cause Mortality

BACKGROUND: This study aimed to determine the association between sedentary time and mortality with regard to leisure‐time physical activity with or without cardiometabolic diseases such as hypertension, dyslipidemia, and diabetes mellitus. METHODS AND RESULTS: Using data from the J‐MICC (Japan Multi‐Institutional Collaborative Cohort) Study, 64 456 participants (29 022 men, 35 434 women) were analyzed. Hazard ratios (HRs) and 95% CIs were used to characterize the relative risk of all‐cause mortality to evaluate its association with sedentary time (categorical variables: <5, 5 to <7, 7 to <9, ≥9 h/d and 2‐hour increments in exposure) according to the self‐reported hypertension, dyslipidemia, and diabetes mellitus using a Cox proportional hazards model. A total of 2257 participants died during 7.7 years of follow‐up. The corresponding HRs for each 2‐hour increment in sedentary time among participants with all factors, no factors, hypertension, dyslipidemia, and diabetes mellitus were 1.153 (95% CI, 1.114–1.194), 1.125 (95% CI, 1.074–1.179), 1.202 (95% CI, 1.129–1.279), 1.176 (95% CI, 1.087–1.273), and 1.272 (95% CI, 1.159–1.396), respectively. Furthermore, when analyzed according to the combined different factors (hypertension, dyslipidemia, and diabetes mellitus), HRs increased with each additional factor, and participants reporting all 3 conditions had the highest HR of 1.417 (95% CI, 1.162–1.728) independently of leisure‐time metabolic equivalents. CONCLUSIONS: The association between sedentary time and increased mortality is stronger among patients with hypertension, dyslipidemia, and diabetes mellitus regardless of leisure‐time physical activity in a large Japanese population

Are the long-term survival, proliferation, and differentiation of transplanted cells desirable in clinical application for spinal cord injury?

Cell transplantation studies of spinal cord injury have a premise that the transplants should be integrated in the host spinal cord tissue, differentiate into neural cells, and re-establish neural circuits, leading to the improvement of locomotor functions. However, the long-term survival, extensive proliferation, and/or differentiation of transplanted cells are not necessarily desirable clinically, and may, on the contrary, cause serious problems regarding the safety of transplants. The excessive proliferation, migration, and/or differentiation of transplanted cells may deteriorate the histological as well as functional organization of the host spinal cord. The present communication will discuss the feasibility of using three kinds of cell as transplants, including bone marrow-derived cells (BMDCs), Schwann cells, and neural stem/progenitor cells (NSPCs). BMDCs enhance tissue recovery and locomotor improvements; however, they disappear within 2-3 weeks after transplantation from the host spinal cord. This indicates that BMDCs do not serve as scaffolds for the growth of regenerating axons, but promote "endogenous" regenerating capacities of the host spinal cord, probably by secreting some trophic factors. This short-term survival of transplants, although appearing to be a disadvantage, guarantees the safety of cell transplantation. The transplantation of BMDCs is now at the Phase I/II stage of clinical application. Schwann cells have been studied extensively as a transplant material for spinal cord injury. Schwann cells survive long-term, and moderately proliferate and/or migrate in the spinal cord. It can be said that Schwann cells become well integrated in the host spinal cord. Therefore, they are regarded as a safe transplant. NSPCs proliferate, migrate, and differentiate extensively after transplantation in the host spinal cord. It is impossible at present to manipulate or control the proliferation/migration/differentiation of NPSCs to make them properly integrate in the host spinal cord. NSPCs are not considered safe for clinical application. BMDCs and Schwann cells are clinically relevant, while NS/PCs are clinically irrelevant

Manipulating histone acetylation leads to antitumor effects in hemangiosarcoma cells

Canine hemangiosarcoma (HSA) is a malignant tumour derived from endothelial cells. No effective treatment has yet been developed because of the lack of understanding of its pathogenesis. Histone acetylation, an epigenetic modification, is highly associated with cancer pathogenesis. Manipulating histone acetylation by histone deacetylase inhibitors (HDACi) or bromodomain and extraterminal domain inhibitors (BETi) is one approach to treat various cancers. However, the role of histone acetylation in HSA remains unknown. This study aimed to investigate how histone acetylation functions in HSA pathogenesis using two HDACi, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), and one BETi, JQ1, in vitro and in vivo. Histone acetylation levels were high in cell lines and heterogeneous in clinical cases. SAHA and JQ1 induced apoptosis in HSA cell lines. HSA cell lines treated with SAHA and VPA upregulated inflammatory-related genes and attracted macrophage cell line RAW264 cells, which suggests that SAHA and VPA can affect immune responses. JQ1 stimulated autophagy and inhibited the cell cycle in HSA cell lines. Finally, we demonstrated that JQ1 suppressed HSA tumour cell proliferation in vivo although SAHA and VPA did not affect tumour growth. These results suggest that BETi can be alternative drugs for HSA treatment. Although further research is required, our study indicated that dysregulation of histone acetylation is likely to be involved in HSA malignancy