ABSTRACT
ZBP1 is an interferon-induced cytosolic nucleic acid sensor that facilitates antiviral responses via RIPK3. Although ZBP1-mediated programmed cell death is widely described, whether and how it promotes inflammatory signaling is unclear. Here, we report a ZBP1-induced inflammatory signaling pathway mediated by K63- and M1-linked ubiquitin chains, which depends on RIPK1 and RIPK3 as scaffolds independently of cell death. In human HT29 cells, ZBP1 associated with RIPK1 and RIPK3 as well as ubiquitin ligases cIAP1 and LUBAC. ZBP1-induced K63- and M1-linked ubiquitination of RIPK1 and ZBP1 to promote TAK1- and IKK-mediated inflammatory signaling and cytokine production. Inhibition of caspase activity suppressed ZBP1-induced cell death but enhanced cytokine production in a RIPK1- and RIPK3 kinase activity-dependent manner. Lastly, we provide evidence that ZBP1 signaling contributes to SARS-CoV-2-induced cytokine production. Taken together, we describe a ZBP1-RIPK3-RIPK1-mediated inflammatory signaling pathway relayed by the scaffolding role of RIPKs and regulated by caspases, which may induce inflammation when ZBP1 is activated below the threshold needed to trigger a cell death response.
ABSTRACT
OBJECTIVES: To explore the impacts of the 2020 New Zealand COVID-19 lockdown on peer-led Steady as You Go (SAYGO) fall prevention exercise classes and members, and to develop recommendations for mitigating impacts during future lockdowns. METHODS: Semi-structured phone interviews were conducted with 20 SAYGO program participants and managers following the first COVID-19 lockdown in New Zealand. Interviews were audio-recorded, transcribed verbatim and analysed using the General Inductive Approach. RESULTS: Participants were between 67 and 88 years of age, predominantly female (90%) and NZ European (80%), with one participant identifying as NZ Maori. Three themes were constructed from the analysis: Personal Function and Well-Being, Class Functioning and Logistics, and Future Strategies for Classes During Prospective Lockdowns. Participants used a range of strategies to stay connected with each other and continue the SAYGO exercises at home. Most participants and peer-leaders reported that they maintained physical function during lockdown, although some had feelings of psychological distress and social isolation. Contact systems and resource distribution varied substantially between groups. Classes resumed post-lockdown with only minor modifications and slightly decreased attendance. CONCLUSIONS: Overall, members of this peer-led model of fall prevention classes demonstrated resilience during the COVID-19 lockdown, despite some challenges. We propose three recommendations to address the challenges of maintaining existing peer-led exercise classes in the context of prospective lockdowns: (1) develop a comprehensive contact detail register and plans for each group; (2) delivery of modified exercise classes remotely over lockdown; and (3) implementation of a nationwide IT education and resource program for older adults.