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

Autophagy. 2013 Oct;9(10):1591-603. doi: 10.4161/auto.26059. Epub 2013 Aug 13.

Abstract

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.

Keywords: NFKB signaling; SQSTM1/p62; cleavage; coxsackievirus; selective autophagy; viral protease 2A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Autophagy / genetics
  • Autophagy / physiology*
  • Enterovirus B, Human / isolation & purification
  • HeLa Cells
  • Humans
  • Microtubule-Associated Proteins / metabolism
  • NF-kappa B p50 Subunit / metabolism
  • Phagosomes / metabolism
  • Sequestosome-1 Protein
  • Signal Transduction / physiology*
  • Transcription Factors / metabolism
  • Ubiquitinated Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Microtubule-Associated Proteins
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Transcription Factors
  • Ubiquitinated Proteins