Title: K63-linked Ubiquitination in the Innate Immune Response
Ubiquitination is a post-translational protein modification that critically regulates initiation,
propagation and termination of the innate immune response. The ubiquitin-conjugating E2 enzyme 13 (Ubc13) catalyzes K63-linked polyubiquitin chains, which have non-proteolytic functions such as
the recruitment of binding partners. Ubc13-mediated ubiquitination plays an important role in NF-κB
signaling and is thus profoundly involved in the immune response pathways.
Here, we show the impact of K63 ubiquitin perturbation on the innate pro-inflammatory and antiviral
immune response. Ablation of Ubc13 in bone marrow-derived macrophages (BMDM) results in a
decreased pro-inflammatory response upon TLR4 activation. In contrast, Ubc13-deficient
macrophages revealed an enhanced type I interferon production upon TLR3 and TLR4 stimulation,
which subsequently increased the activation of the STAT1 signaling and interferon-stimulated gene
(ISG) expression. Moreover, mice with a deletion of Ubc13 in macrophages show a robust immune
response against RNA virus infections such as lymphocytic choriomeningitis virus (LCMV) and SARS-
Taken together, these results show that Ubc13 limits type I IFN production in macrophages and is a
critical regulator of antiviral immunity.
Keywords: ubiquitination, innate immunity, macrophages, antiviral immunity, infectious diseases,
type I interferons