The E2 polyubiquitin-conjugating enzyme Ubc13 is a mediator of innate immune 
reactions. Ubc13 mediates the conjugation of keratin (K)63-linked polyubiquitin 
chains onto TNF receptor-associated factor 6 and IKKγ during NF-κB activation. 
In contrast to K48-linked polyubiquitin chains, K63-linked polyubiquitin chains 
function in nonproteasomal biological processes. Although Ubc13 has been shown 
to be critical for Toll-like receptor (TLR) and IL-1 receptor signaling, the 
function of Ubc13 in the epidermis has not been studied. We generated 
keratinocyte-specific Ubc13-deficient mice (Ubc13(flox/flox)K5-Cre). At birth, 
the skin of the Ubc13(flox/flox)K5-Cre mice was abnormally shiny and smooth; in 
addition, the mice did not grow and died by postnatal day 2. Histological 
analysis showed atrophy of the epidermis with keratinocyte apoptosis. 
Immunohistochemical analyses revealed reduced proliferation, abnormal 
differentiation, and apoptosis of keratinocytes in the Ubc13(flox/flox)K5-Cre 
mouse epidermis. In culture, Ubc13(flox/flox)K5-Cre keratinocyte growth was 
impaired, and spontaneous cell death occurred. Moreover, the deletion of Ubc13 
from cultured Ubc13(flox/flox) keratinocytes by means of an adenoviral vector 
carrying Cre recombinase also resulted in spontaneous cell death. Therefore, 
Ubc13 is essential for keratinocyte growth, differentiation, and survival. 
Analyses of intracellular signaling revealed that the IL-1 and TNF-induced 
activation of JNK, p38, and NF-κB pathways was impaired in 
Ubc13(flox/flox)K5-Cre keratinocytes. In conclusion, Ubc13 appears to be 
essential for epidermal integrity in mice.