SHARPIN is a critical component of the linear ubiquitin chain assembly complex (LUBAC), which conjugates linear polyubiquitin chains to substrates and plays essential roles in NF-κB activation and immune regulation 1. As part of LUBAC, SHARPIN contributes to canonical NF-κB signaling by conjugating linear polyubiquitin to key proteins like IKBKG and RIPK1, interfering with TNF-induced cell death and preventing excessive inflammation 2. The complex is recruited to TNF-R1 signaling complexes following polyubiquitination, contributing to complex stability 2. Beyond immune signaling, SHARPIN participates in autophagy regulation through linear ubiquitination and stabilization of ATG13, controlling both autophagy initiation and maturation 3. SHARPIN deficiency causes severe immunological consequences in humans, manifesting as autoinflammation and immunodeficiency with attenuated canonical NF-κB responses and increased susceptibility to cell death mediated by TNF superfamily members 1. Clinical management with anti-TNF therapies has shown complete resolution of autoinflammatory symptoms in SHARPIN-deficient patients 1. Additionally, genetic variants in SHARPIN have been associated with Alzheimer's disease risk, suggesting broader roles in neurodegeneration 4.