Two proteases, trypsin domain-containing 1 (Tysnd1) and peroxisomal lon protease (PsLon), cooperatively regulate fatty acid β-oxidation in peroxisomal matrix

J Biol Chem. 2011 Dec 30;286(52):44367-79. doi: 10.1074/jbc.M111.285197. Epub 2011 Oct 14.


The molecular mechanisms underlying protein turnover and enzyme regulation in the peroxisomal matrix remain largely unknown. Trypsin domain-containing 1 (Tysnd1) and peroxisomal Lon protease (PsLon) are newly identified peroxisomal matrix proteins that harbor both a serine protease-like domain and a peroxisome-targeting signal 1 (PTS1) sequence. Tysnd1 processes several PTS1-containing proteins and cleaves N-terminal presequences from PTS2-containing protein precursors. Here we report that knockdown of Tysnd1, but not PsLon, resulted in accumulation of endogenous β-oxidation enzymes in their premature form. The protease activity of Tysnd1 was inactivated by intermolecular self-conversion of the 60-kDa form to 15- and 45-kDa chains, which were preferentially degraded by PsLon. Peroxisomal β-oxidation of a very long fatty acid was significantly decreased by knockdown of Tysnd1 and partially lowered by PsLon knockdown. Taken together, these data suggest that Tysnd1 is a key regulator of the peroxisomal β-oxidation pathway via proteolytic processing of β-oxidation enzymes. The proteolytic activity of oligomeric Tysnd1 is in turn controlled by self-cleavage of Tysnd1 and degradation of Tysnd1 cleavage products by PsLon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism
  • Fatty Acids / genetics
  • Fatty Acids / metabolism*
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Oxidation-Reduction
  • Peroxisomes / enzymology*
  • Peroxisomes / genetics
  • Protein Sorting Signals / physiology
  • Protein Structure, Tertiary
  • Proteolysis*
  • Serine Endopeptidases
  • Serine Proteases / genetics
  • Serine Proteases / metabolism*


  • Enzyme Precursors
  • Fatty Acids
  • Protein Sorting Signals
  • PsLon protein, human
  • Serine Proteases
  • Serine Endopeptidases
  • Tysnd1 protein, human
  • Cysteine Endopeptidases