SLIM trims STATs: ubiquitin E3 ligases provide insights for specificity in the regulation of cytokine signaling.

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway has evolved to serve highly specialized functions in the regulation of hematopoiesis, cell metabolism, and immune responses. The duration, strength, and specificity of cytokine signaling are controlled by several mechanisms, including the ubiquitin-proteasome pathway, which modulates the turnover of cytokine receptors and activated JAKs. The specificity of the ubiquitin pathway is achieved through various E3 ligase complexes that recognize and interact with distinct target proteins, often in a phosphorylation-dependent manner. Intriguing new information about the ubiquitin pathway came with the identification of an E3 ubiquitin ligase, SLIM, that specifically interacts with activated STAT1 and STAT4 and induces their ubiquitination and degradation. These findings, together with the evidence from paramyxoviruses about the role of ubiquitination as a highly specific STAT inhibition mechanism, highlight the role of E3 ubiquitin ligases as specificity determinants in the regulation of STAT activation, and open the field for investigation of additional E3s that target other STAT proteins.