A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S phase and processes the CDP/Cux transcription factor.
The subclass of cysteine proteases termed lysosomal cathepsins has long been thought to be primarily involved in end-stage protein breakdown within lysosomal compartments. Furthermore, few specific protein substrates for these proteases have been identified. We show here that cathepsin L functions in the regulation of cell cycle progression through proteolytic processing of the CDP/Cux transcription factor. CDP/Cux processing in situ was increased following ectopic expression of cathepsin L but was reduced in Cat L(-/-) cells. Furthermore, catalytically active cathepsin L was localized to the nucleus during the G1-S transition as detected by immunofluorescence imaging and labeling using activity-based probes. Trafficking of cathepsin L to the nucleus is accomplished through a mechanism involving translation initiation at downstream AUG sites and the synthesis of proteases that are devoid of a signal peptide. Overall, these results uncover an as yet unsuspected role for cysteine proteases in the control of cell cycle progression.
Goulet
Brigitte
B
Department of Biochemistry, McGill University, 687 Pine Avenue West, Montreal H3A 1A1, Canada.
Baruch
Amos
A
Moon
Nam-Sung
NS
Poirier
Madeleine
M
Sansregret
Laurent L
LL
Erickson
Ann
A
Bogyo
Matthew
M
Nepveu
Alain
A
D000818:Animals; D002384:Catalysis; D056668:Cathepsin L; D002403:Cathepsins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002457:Cell Extracts; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism*; D002738:Chloroquine / Q000494:pharmacology; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D019084:Fluorescent Antibody Technique, Indirect; D018398:Homeodomain Proteins; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021382:Protein Sorting Signals; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D013347:Subcellular Fractions
D002457:Cell Extracts; C000624101:Cux1 protein, mouse; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D018398:Homeodomain Proteins; D007976:Leupeptins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D021382:Protein Sorting Signals; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012097:Repressor Proteins; C412454:phenylalanyl-glycyl-NHO-Bz; D002738:Chloroquine; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde