Shi J, Wong J, Piesik P, Fung G, Zhang J, Jagdeo J, Li X, Jan E, Luo H

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 ...

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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.

Date: Aug. 13, 2013

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