UBE2L6

UBE2L6 Full Name

ubiquitin-conjugating enzyme E2L 6

UBE2L6 Introduction

UBE2L6, also known as UbcH8, is a ~17 kDa ubiquitin-conjugating (E2) enzyme that serves as the dedicated E2 for the interferon (IFN)-induced ISG15 conjugation system. In this pathway, UBE2L6 receives ISG15 from the E1 enzyme UBA7 and, together with the HECT E3 ligase HERC5, transfers it onto substrate proteins. ISGylation is transcriptionally induced by type I IFN and modifies hundreds of cellular and viral proteins, functioning primarily as an antiviral restriction mechanism rather than a degradation signal. Importantly, the selectivity of UBE2L6 for this cascade is dictated by structural features of its interface with UBA7; a discrete set of contacts—distinct from those used by its close paralog UBE2L3—stabilizes the E1-E2 pairing and explains why UBE2L6, and not UBE2L3, is preferentially recruited into the ISG15 pathway. Although best characterized in ISGylation, UBE2L6/UbcH8 can also participate in canonical ubiquitination with selected E3 ligases, underscoring the mechanistic overlap between the ubiquitin and ISG15 systems that share E1 and E2 components.

Figure 1. Intracellular mechanism pathway of UBE2L6. (Source: Gao J, et al. 2021)

Beyond its role as a conjugating enzyme, UBE2L6 exemplifies how a single E2 can mediate crosstalk between ubiquitin-like pathways. The ISG15 system can modify other ubiquitin-conjugating enzymes; for example, ISGylation of Ubc13 suppresses its ubiquitin-conjugating activity, dampening downstream ubiquitination and revealing direct feedback between the two modification systems. Because both ISG15 and its conjugation enzymes are strongly induced by type I IFN, UBE2L6 functions as a tightly regulated node that couples antiviral signaling to broader control of protein modification. Its pronounced induction during infection and its centrality to ISGylation make UBE2L6 a useful marker of IFN activation and a focal point for host–pathogen interactions, since numerous viruses encode de-ISGylating activities that specifically counteract this host defense. Collectively, these properties place UBE2L6 at the intersection of innate immunity and the ubiquitin machinery.

Alternate Names for UBE2L6

UBE2L6; ubiquitin-conjugating enzyme E2L 6; RIG-B; UBCH8; ubiquitin/ISG15-conjugating enzyme E2 L6; ubiquitin-protein ligase L6; ubiquitin carrier protein L6; retinoic acid induced gene B protein; retinoic acid-induced gene B protein;

• 1. Gao J, et al. Increased UBE2L6 regulated by type 1 interferon as potential marker in TB. J Cell Mol Med. 2021 Dec;25(24):11232-11243.
  2. Zhao C, et al. The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN-alpha/beta-induced ubiquitin-like protein. Proc Natl Acad Sci U S A. 2004 May 18;101(20):7578-82.