Calpains promote α2β1 integrin turnover in nonrecycling integrin pathway

Abstract

A novel virus- and integrin clustering–specific pathway diverts integrin from its normal endo/exocytic traffic to a nonrecycling degradative endosomal route. Clustering of α2β1 integrin causes redistribution of the integrin to perinuclear endosomes, leading to enhanced integrin turnover promoted by calpains.

RNAi screen identifies KIF15 as a novel regulator of integrin endocytic trafficking

“…By contrast, antibody-clustered a2 integrin (see Methods) accumulated in cytoplasmic punctate structures with hardly any residual plasma membrane localization (Fig. 1C), as reported previously (Rintanen et al, 2012;Karjalainen et al, 2008;Upla et al, 2004).…”

“…Alternatively, our data opens an intriguing possibility that clathrin-and caveolin-dependent mechanisms might act in a sequential manner. Nevertheless, the endocytic route of unbound a2 integrin differs strongly from the calpaindependent degradation pathway taken by the antibody-clustered a2 integrin (Rintanen et al, 2012). With the goal of defining a substantial proportion of the proteins affecting the cell-surface expression of a2 integrin, we performed a fluorescent microscopy-based RNAi screen (Fig.…”

“…The majority of the internalized integrins are recycled back to the plasma membrane (Caswell and Norman, 2006) either through Rab11-specific (long-loop) or Rab4-specific (short-loop) pathways (Roberts et al, 2001;Powelka et al, 2004;Arjonen et al, 2012). Ligand-bound integrins can also be directed to lysosomal or non-lysosomal degradation pathways (Arjonen et al, 2012;Valdembri et al, 2009;Rintanen et al, 2012;Lobert et al, 2010;Tiwari et al, 2011b;Dozynkiewicz et al, 2012). Competitive binding of diverse regulators to integrins might promote recycling or intracellular retention (Mai et al, 2011;Böttcher et al, 2012).…”

“…a2b1 integrin also acts as a co-receptor for several pathogens, such as echovirus 1 (EV1), rotavirus and human cytomegalovirus (Bergelson et al, 1992;Londrigan et al, 2003;Feire et al, 2004;Fleming et al, 2011). Binding of EV1 induces clustering of inactive a2b1 and directs virus-bound a2 integrin to a calpain-dependent degradation pathway in multivesicular bodies (Rintanen et al, 2012;Karjalainen et al, 2008;Upla et al, 2004). Binding of a2b1 integrin to collagen might direct the heterodimer to the same degradation pathway (Rintanen et al, 2012).…”

“…Binding of EV1 induces clustering of inactive a2b1 and directs virus-bound a2 integrin to a calpain-dependent degradation pathway in multivesicular bodies (Rintanen et al, 2012;Karjalainen et al, 2008;Upla et al, 2004). Binding of a2b1 integrin to collagen might direct the heterodimer to the same degradation pathway (Rintanen et al, 2012). By contrast, little is known about the trafficking route of non-clustered a2b1 integrin, apart from a role for Rab21 binding to the a2 integrin cytoplasmic tail to facilitate endocytosis and a role for binding of the p120 RasGAP (GTPase activating protein; also known as RASA1), which facilitates the recycling of a2b1 integrin to the plasma membrane (Mai et al, 2011).…”