Sensing of viral RNA by the cytosolic receptors RIG-I and melanoma 
differentiation-associated gene 5 (MDA5) leads to innate antiviral response. How 
RIG-I and MDA5 are dynamically regulated in innate antiviral response is not 
well understood. Here, we show that TRIM38 positively regulates MDA5- and 
RIG-I-mediated induction of downstream genes and acts as a SUMO E3 ligase for 
their dynamic sumoylation at K43/K865 and K96/K888, respectively, before and 
after viral infection. The sumoylation of MDA5 and RIG-I suppresses their 
K48-linked polyubiquitination and degradation in uninfected or early-infected 
cells. Sumoylation of the caspase recruitment domains of MDA5 and RIG-I is also 
required for their dephosphorylation by PP1 and activation upon viral infection. 
At the late phase of viral infection, both MDA5 and RIG-I are desumoylated by 
SENP2, resulting in their K48-linked polyubiquitination and degradation. These 
findings suggest that dynamic sumoylation and desumoylation of MDA5 and RIG-I 
modulate efficient innate immunity to RNA virus and its timely termination.