<p>The autoimmune regulator (AIRE) is expressed in medullary thymic epithelial cells (mTECs) and is crucial for generating an immunocompetent T cell repertoire during central tolerance. Loss of AIRE function causes autoimmune polyglandular syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Intracellular proteins are regulated by ubiquitination pathways. E3 ubiquitin ligases are specific proteins that confer selectivity to polyubiquitination, tagging proteins for proteasomal degradation while also performing other functions. In mTECs, peptides generated via the class I antigen-processing pathway are presented by HLA-I molecules to CD8 thymocytes to eliminate self-reactive T-cell precursors. AIRE induces promiscuous gene expression in mTECs, but little is known about the regulatory mechanisms of AIRE. Previously, we and others demonstrated that AIRE is an apoptosis inductor. Here, we demonstrate that AIRE increases the intracellular levels of SIAH-interacting protein (SIP), an adaptor protein of the SIAH E3 ubiquitin ligase family. We also show that AIRE interacts with SIAH1 in the human thymus. While AIRE contains two putative SIAH-interacting motifs, it interacts with SIAH proteins only through the sequence spanning residues 119–125. AlphaFold modeling indicated that the interaction between AIRE and SIAH1 is highly analogous to that observed between SIP and SIAH1, suggesting that both proteins compete for SIAH1 binding. The CARD domain and the SIAH-interacting motif is required to AIRE-mediated apoptosis. AIRE co-localized with SIAH proteins in the cytoplasm of HEK-293 cells. Finally, SIAH1 ubiquitinated AIRE, targeting it for proteasomal degradation. Collectively, these findings reveal a novel pathway for the degradation and regulation of AIRE.</p>