The 3'UTR of the α6 integrin message regulates localization of α6β4 integrin heterodimers.

The α6β4 integrin heterodimer is an essential component of hemidesmosomes (HDs) and HD-related structures, which adhere epithelial cells to the underlying extracellular matrix. In this study, we focused on the importance of the α6 integrin 3' untranslated region (UTR) in α6β4 integrin localization. To do so, A549 cells (a type II lung alveolar cell line) and immortalized human epidermal keratinocytes (iHEK) were infected with adenovirus encoding the entire α6 integrin protein with or without portions of its 3'UTR. In infected A549 cells, we detected α6β4 integrin heterodimers containing the product of the adenovirus, regardless of whether the α6 integrin 3'UTR was present. However, only those α6 integrin proteins whose messages contained bases 4770-5633 of the α6 integrin 3'UTR were targeted to matrix adhesion sites. Moreover, overexpression of the full length α6 integrin 3'UTR, minus the coding sequence, in A549 cells disrupts the localization of endogenous α6β4 integrin heterodimers. Following infection of iHEKs with the same adenovirus, the induced α6 integrin protein localizes to HDs regardless of whether its message possessed a 3'UTR. In sharp contrast, in α6 integrin depleted iHEKs, restoring α6 integrin expression using the coding sequence alone via adenoviral transduction resulted in α6 integrin preferentially forming α6β1 rather than α6β4 integrin heterodimers. α6β4 integrin was only observed in knocked down cells following infection of adenovirus encoding the α6 integrin coding sequence with its 3'UTR. In summary, our data indicate that the α6 integrin 3'UTR is a key regulator of α6β4 integrin heterodimer assembly and incorporation at sites of cell-matrix adhesion.