The E3 Ubiquitin Protein Ligase LINCR Amplifies the TLR-Mediated Signals through Direct Degradation of MKP1.

Toll-like receptors (TLRs) induce innate immune responses through activation of intracellular signaling pathways, such as MAP kinase and NF-κB signaling pathways, and play an important role in host defense against bacterial or viral infections. Meanwhile, excessive activation of TLR signaling leads to a variety of inflammatory disorders, including autoimmune diseases. TLR signaling is therefore strictly controlled to balance optimal immune response and inflammation. However, its balancing mechanisms are not fully understood. In this study, we identified the E3 ubiquitin ligase LINCR/ NEURL3 as a critical regulator of TLR signaling. In LINCR-deficient cells, the sustained activation of JNK and p38 MAPKs induced by the agonists for TLR3, TLR4, and TLR5, was clearly attenuated. Consistent with these observations, TLR-induced production of a series of inflammatory cytokines was significantly attenuated, suggesting that LINCR positively regulates innate immune responses by promoting the activation of JNK and p38. Interestingly, our further mechanistic study identified MAPK phosphatase-1 (MKP1), a negative regulator of MAP kinases, as a ubiquitination target of LINCR. Thus, our results demonstrate that TLRs fine-tune the activation of MAP kinase pathways by balancing LINCR (the positive regulator) and MKP1 (the negative regulator), which may contribute to the induction of optimal immune responses.

Nuclear-accumulated SQSTM1/p62-based ALIS act as microdomains sensing cellular stresses and triggering oxidative stress-induced parthanatos.

Aggresome-like induced structures (ALIS) have been described as ubiquitinated protein-containing aggresomes transiently formed in response to various stresses. In this study, we provide evidence that ALIS composed of SQSTM1/p62 act as a key determinant of oxidative stress-induced parthanatos, which is newly discovered and distinct from regular programmed cell death. Interestingly, we first found that chemical stresses induced by particular chemical drugs, such as several cephalosporin antibiotics, cause oxidative stress-mediated parthanatos, accompanied by the ALIS formation. Blocking the ALIS formation potently suppressed the parthanatos, and p62 knockout cells exhibited the attenuated ALIS formation and high resistance to parthanatos. Moreover, we also found that the redox-sensing activity of p62 is required for nuclear accumulation of the p62-based ALIS, resulting in the induction of parthanatos. Together, our results demonstrate unexpected functions of p62 and ALIS as cell death mediators sensing oxidative stress, and thus uncover a novel mechanism whereby p62 mediates parthanatos.