title: Calpains promote α2β1 integrin turnover in nonrecycling integrin pathway.
abstract: Collagen receptor integrins recycle between the plasma membrane and endosomes and facilitate formation and turnover of focal adhesions. In contrast, clustering of α2β1 integrin with antibodies or the human pathogen echovirus 1 (EV1) causes redistribution of α2 integrin to perinuclear multivesicular bodies, α2-MVBs. We show here that the internalized clustered α2 integrin remains in α2-MVBs and is not recycled back to the plasma membrane. Instead, receptor clustering and internalization lead to an accelerated down-regulation of α2β1 integrin compared to the slow turnover of unclustered α2 integrin. EV1 infection or integrin degradation is not associated with proteasomal or autophagosomal processes and shows no significant association with lysosomal pathway. In contrast, degradation is dependent on calpains, such that it is blocked by calpain inhibitors. We show that active calpain is present in α2-MVBs, internalized clustered α2β1 integrin coprecipitates with calpain-1, and calpain enzymes can degrade α2β1 integrin. In conclusion, we identified a novel virus- and clustering-specific pathway that diverts α2β1 integrin from its normal endo/exocytic traffic to a nonrecycling, calpain-dependent degradative endosomal route.
authors.affiliation: Department of Biological and Environmental Science/Nanoscience Center, University of Jyväskylä, FI-40351 Jyväskylä, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Rintanen
authors.forename: Mikko
authors.initials: M
authors.lastname: Karjalainen
authors.forename: Jonna
authors.initials: J
authors.lastname: Alanko
authors.forename: Lassi
authors.initials: L
authors.lastname: Paavolainen
authors.forename: Anita
authors.initials: A
authors.lastname: Mäki
authors.forename: Liisa
authors.initials: L
authors.lastname: Nissinen
authors.forename: Moona
authors.initials: M
authors.lastname: Lehkonen
authors.forename: Katri
authors.initials: K
authors.lastname: Kallio
authors.forename: R Holland
authors.initials: RH
authors.lastname: Cheng
authors.forename: Paula
authors.initials: P
authors.lastname: Upla
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
authors.forename: Varpu
authors.initials: V
authors.lastname: Marjomäki
mesh_terms: D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D029822:Enterovirus B, Human / Q000378:metabolism; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism; D006801:Humans; D038982:Integrin alpha2beta1 / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D038982:Integrin alpha2beta1; D002154:Calpain