Here we have identified host cell proteins involved with the cellular 
SUMOylation pathway, SUMO-1 (small ubiquitin-like modifier) and UBC9, a SUMO-1 
conjugating enzyme that interact with classical swine fever virus (CSFV) Core 
protein. Five highly conserved lysine residues (K179, K180, K220, K221, and 
K246) within the CSFV Core were identified as putative SUMOylation sites. 
Analysis of these interactions showed that K179A, K180A, and K221A substitutions 
disrupt Core-SUMO-1 binding, while K220A substitution precludes Core-UBC9 
binding. In vivo, Core mutant viruses (K179A, K180A, K220A, K221A) and (K220A, 
K221A) harboring those substitutions were attenuated in swine. These data shows 
a clear correlation between the disruption of Core protein binding to SUMO-1 and 
UBC9 and CSFV attenuation. Overall, these data suggest that the interaction of 
Core with the cellular SUMOylation pathway plays a significant role in the CSFV 
growth cycle in vivo.