title: Cleavage of sequestosome 1/p62 by an enteroviral protease results in disrupted selective autophagy and impaired NFKB signaling.
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.
authors.affiliation: James Hogg Research Center; Providence Heart + Lung Institute; St. Paul's Hospital and Department of Pathology and Laboratory Medicine; University of British Columbia; Vancouver, BC Canada.
authors.forename: Junyan
authors.initials: J
authors.lastname: Shi
authors.affiliation: James Hogg Research Center; Providence Heart + Lung Institute; St. Paul's Hospital and Department of Pathology and Laboratory Medicine; University of British Columbia; Vancouver, BC Canada.
authors.forename: Jerry
authors.initials: J
authors.lastname: Wong
authors.affiliation: James Hogg Research Center; Providence Heart + Lung Institute; St. Paul's Hospital and Department of Pathology and Laboratory Medicine; University of British Columbia; Vancouver, BC Canada.
authors.forename: Paulina
authors.initials: P
authors.lastname: Piesik
authors.affiliation: James Hogg Research Center; Providence Heart + Lung Institute; St. Paul's Hospital and Department of Pathology and Laboratory Medicine; University of British Columbia; Vancouver, BC Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Fung
authors.affiliation: James Hogg Research Center; Providence Heart + Lung Institute; St. Paul's Hospital and Department of Pathology and Laboratory Medicine; University of British Columbia; Vancouver, BC Canada.
authors.forename: Jingchun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology; University of British Columbia; Vancouver, BC Canada.
authors.forename: Julienne
authors.initials: J
authors.lastname: Jagdeo
authors.affiliation: Institutes of Biomedical Sciences; East China Normal University; Shanghai, China; Department of Molecular and Cellular Biology; Baylor College of Medicine; Houston, TX USA.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology; University of British Columbia; Vancouver, BC Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Jan
authors.affiliation: James Hogg Research Center; Providence Heart + Lung Institute; St. Paul's Hospital and Department of Pathology and Laboratory Medicine; University of British Columbia; Vancouver, BC Canada.
authors.forename: Honglin
authors.initials: H
authors.lastname: Luo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D029822:Enterovirus B, Human / Q000302:isolation & purification; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008869:Microtubule-Associated Proteins; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014157:Transcription Factors; D057149:Ubiquitinated Proteins
keywords: NFKB signaling; SQSTM1/p62; cleavage; coxsackievirus; selective autophagy; viral protease 2A