Cleavage of sequestosome 1/p62 by an enteroviral protease results in disrupted selective autophagy and impaired NFKB signaling

• Published in: Autophagy 2013-10, Vol.9 (10), p.1591-1603
• Main Authors: Shi, Junyan, Wong, Jerry, Piesik, Paulina, Fung, Gabriel, Zhang, Jingchun, Jagdeo, Julienne, Li, Xiaotao, Jan, Eric, Luo, Honglin
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Autophagy - genetics; Autophagy - physiology; cleavage; coxsackievirus; Enterovirus B, Human - isolation & purification; HeLa Cells; Humans; Microtubule-Associated Proteins - metabolism; NF-kappa B p50 Subunit - metabolism; NFKB signaling; Phagosomes - metabolism; selective autophagy; Sequestosome-1 Protein; Signal Transduction - physiology; SQSTM1/p62; Transcription Factors - metabolism; Ubiquitinated Proteins - metabolism; viral protease 2A
• ISSN: 1554-8627; 1554-8635
• DOI: 10.4161/auto.26059

The adaptor protein, sequestosome 1 (SQSTM1)/p62, plays an essential role in mediating selective autophagy. It serves as an autophagy receptor targeting ubiquitinated proteins to autophagosomes for degradation. In addition, it functions as a scaffold protein to regulate signaling pathways. Here we explored the interplay between coxsackievirus B3 (CVB3) and SQSTM1-mediated selective autophagy. We reported that SQSTM1 was cleaved at glycine 241 following CVB3 infection through the activity of viral protease 2A pro . The resulting cleavage fragments of SQSTM1 were no longer the substrates of autophagy, and their ability to form protein aggregates was greatly decreased. Although the C-terminal truncation sustained the binding activity of SQSTM1 to microtubule-associated protein 1 light chain (LC3), it failed to interact with ubiquitinated proteins. It was also found that colocalization between the C-terminal fragment of SQSTM1 (SQSTM1-C) and LC3 and ubiquitin within the punctate structures was markedly disrupted. Moreover, we observed that SQSTM1-C retained the ability of SQSTM1 to stabilize antioxidant transcription factor NFE2L2 [nuclear factor (erythroid-derived 2)-like 2]; however, both the N-terminal fragment of SQSTM1 (SQSTM1-N) and SQSTM1-C lost the function of SQSTM1 in activating NFKB (the nuclear factor of kappa light polypeptide gene enhancer in B-cells) pathway. Collectively, our results suggest a novel model by which cleavage of SQSTM1 as a result of CVB3 infection impairs the function of SQSTM1 in selective autophagy and host defense signaling.