Ubiquitin ligase SYVN1/HRD1 facilitates degradation of the SERPINA1 Z variant/α-1-antitrypsin Z variant via SQSTM1/p62-dependent selective autophagy

Autophagy. 2017 Apr 3;13(4):686-702. doi: 10.1080/15548627.2017.1280207. Epub 2017 Jan 25.


SERPINA1/AAT/α-1-antitrypsin (serpin family A member 1) deficiency (SERPINA1/ AAT-D) is an autosomal recessive disorder characterized by the retention of misfolded SERPINA1/AAT in the endoplasmic reticulum (ER) of hepatocytes and a significant reduction of serum SERPINA1/AAT level. The Z variant of SERPINA1/AAT, containing a Glu342Lys (E342K) mutation (SERPINA1E342K/ATZ), the most common form of SERPINA1/AAT-D, is prone to misfolding and polymerization, which retains it in the ER of hepatocytes and leads to liver injury. Both proteasome and macroautophagy/autophagy pathways are responsible for disposal of SERPINA1E342K/ATZ after it accumulates in the ER. However, the mechanisms by which SERPINA1E342K/ATZ is selectively degraded by autophagy remain unknown. Here, we showed that ER membrane-spanning ubiquitin ligase (E3) SYVN1/HRD1 enhances the degradation of SERPINA1E342K/ATZ through the autophagy-lysosome pathway. We found that SYVN1 promoted SERPINA1E342K/ATZ, especially Triton X 100-insoluble SERPINA1E342K/ATZ clearance. However, the effect of SYVN1 in SERPINA1E342K/ATZ clearance was impaired after autophagy inhibition, as well as in autophagy-related 5 (atg5) knockout cells. On the contrary, autophagy induction enhanced SYVN1-mediated SERPINA1E342K/ATZ degradation. Further study showed that SYVN1 mediated SERPINA1E342K/ATZ ubiquitination, which is required for autophagic degradation of SERPINA1E342K/ATZ by promoting the interaction between SERPINA1E342K/ATZ and SQSTM1/p62 for formation of the autophagy complex. Interestingly, SYVN1-mediated lysine 48 (K48)-linked polyubiquitin chains that conjugated onto SERPINA1E342K/ATZ might predominantly bind to the ubiquitin-associated (UBA) domain of SQSTM1 and couple the ubiquitinated SERPINA1E342K/ATZ to the lysosome for degradation. In addition, autophagy inhibition attenuated the suppressive effect of SYVN1 on SERPINA1E342K/ATZ cytotoxicity, and the autophagy inducer rapamycin enhanced the suppressive effect of SYVN1 on SERPINA1E342K/ATZ-induced cell apoptosis. Therefore, this study proved that SYVN1 enhances SERPINA1E342K/ATZ degradation through SQSTM1-dependent autophagy and attenuates SERPINA1E342K/ATZ cytotoxicity.

Keywords: SQSTM1/p62; SYVN1/HRD1; autophagy; protein degradation; ubiquitination; α 1-antitrypsin Z variant.

MeSH terms

  • Animals
  • Autophagy*
  • Cell Death
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Lysine / metabolism
  • Lysosomes / metabolism
  • Mice
  • Models, Biological
  • Polyubiquitin / metabolism
  • Protein Binding
  • Proteolysis*
  • Sequestosome-1 Protein / metabolism*
  • Signal Transduction
  • Solubility
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • alpha 1-Antitrypsin / metabolism*


  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • alpha 1-Antitrypsin
  • Polyubiquitin
  • SYVN1 protein, human
  • Syvn1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Lysine