Optineurin, an autophagy adaptor, stabilizes Rictor to maintain Akt/mTOR signaling and antigen presentation

Optineurin (OPTN) is widely recognized as a multifunctional selective autophagy receptor involved in cargo turnover. However, our recent findings uncover an unexpected function of OPTN that challenges the conventional view of autophagy adaptors. In dendritic cells (DCs), OPTN binds to and stabilizes Rictor, a key component of the mTORC2 complex. Loss of OPTN leads to depletion of Rictor, reduced Akt2 activity, and activation of the mTORC1/p70S6K1 pathway, culminating in enhanced phosphorylation of STAT3 at Ser727. Activated STAT3 transcriptionally induces the E3 ubiquitin ligase MARCH1, which promotes MHC II internalization, resulting in a striking inverse relationship between MARCH1 and MHC II expression in Optn-deficient cells. Together, these findings identify an unexpected signaling function of OPTN, independent of its canonical autophagy activities. By stabilizing Rictor and maintaining mTORC2-Akt2 signaling, OPTN links a classical autophagy adaptor to the regulation of antigen presentation and adaptive immunity. More broadly, our findings raise the possibility that selective autophagy receptors preserve cellular homeostasis not only through cargo clearance but also through context-dependent, non-degradative regulation of protein stability and signaling networks.Abbreviation: OPTN: Optineurin; mTORC1: mammalian target of rapamycin complex 1; mTORC2: mammalian target of rapamycin complex 1; Rictor: Rapamycin-Insensitive Companion of mTOR.