Enhanced ISGylation promotes basal and infection-induced autophagy via mammalian target of rapamycin (mTOR), WD repeat domain, phosphoinositide interacting 2 (WIPI2), activating molecule in Beclin-1-regulated autophagy (AMBRA1), and Ras-related protein (RAB7) modifications, suggesting that ISGylation of metabolic enzymes temporally reprograms organismal metabolism following infection in the liver. The gene discussed is WIPI2; the disease is infection.