A Previously Unreported Function of beta B-1 Integrin Isoform in Caspase-8-Dependent Integrin-Mediated Keratinocyte Death

作者：Lotti Roberta; Marconi Alessandra; Truzzi Francesca; Dallaglio Katiuscia; Gemelli Claudia; Borroni Riccardo G; Palazzo Elisabetta; Pincelli Carlo^*

来源：Journal of Investigative Dermatology, 2010, 130(11): 2569-2577.

DOI：10.1038/jid.2010.195

Integrins regulate adhesive cell-matrix interactions and mediate survival signals. On the other hand, unligated or free cytoplasmic fragments of integrins induce apoptosis in many cell types (integrin-mediated death). We have previously shown that beta(1) integrin expression protects keratinocyte stem cells from anoikis, whereas the role of the beta B-1 integrin isoform has not been clarified. In this study we report that suspended keratinocytes undergo apoptosis through the activation of caspase-8, independently of the Fas/Fas ligand system. Indeed, anti-beta(1) integrin-neutralizing antibodies induced apoptosis in short hairpin RNA Fas-associated death domain-treated cells. Moreover, before and during suspension, caspase-8 directly associated with beta(1) integrin, which in turn internalized and progressively degraded, shedding the cytoplasmic domain. beta B-1 was expressed only in the cytoplasm in a perinuclear manner and remained unaltered during suspension. At 24 hours, as beta(1)A was located close to the nucleus, beta B-1 colocalized with beta(1)A and coimmunoprecipitated with caspase-8. Caspase-8 was activated earlier in beta B-1 integrin-transfected keratinocytes, and these cells underwent a higher rate of apoptosis than mock cells. In contrast, caspase-8 was not activated in small interfering RNA (siRNA) beta B-1-transfected cells. These results indicate that when beta(1)A is unligated, beta B-1 is responsible for "integrin-mediated death" in human keratinocytes.

• 出版日期2010-11