Mechanistic insights into the enzymatic activity of E3 ligase HOIL-1L and its regulation by the linear ubiquitin chain binding

Xu, Xiaolong; Wang, Yaru; Zhang, Yan; Wang, Yingli; Yin, Yue; Peng, Chao; Gong, Xinyu; Li, Miao; Zhang, Yuchao; Zhang, Mingfang; Tang, Yubin; Zhou, Xindi; Liu, Haobo; Pan, Lifeng

doi:10.1126/sciadv.adi4599

Cited by 2 publications

References 65 publications

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Catalysis of non-canonical protein ubiquitylation by the ARIH1 ubiquitin ligase

Purser,

Tripathi-Giesgen,

et al. 2023

Biochemical Journal

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Protein ubiquitylation typically involves isopeptide bond formation between the C-terminus of ubiquitin to the side-chain amino group on Lys residues. However, several ubiquitin ligases (E3s) have recently been identified that ubiquitylate proteins on non-Lys residues. For instance, HOIL-1 belongs to the RING-in-between RING (RBR) class of E3s and has an established role in Ser ubiquitylation. Given the homology between HOIL-1 and ARIH1, an RBR E3 that functions with the large superfamily of cullin-RING E3 ligases (CRLs), a biochemical investigation was undertaken, showing ARIH1 catalyzes Ser ubiquitylation to CRL-bound substrates. However, the efficiency of ubiquitylation was exquisitely dependent on the location and chemical environment of the Ser residue within the primary structure of the substrate. Comprehensive mutagenesis of the ARIH1 Rcat domain identified residues whose mutation severely impacted both oxyester and isopeptide bond formation at the preferred site for Ser ubiquitylation while only modestly affecting Lys ubiquitylation at the physiological site. The results reveal dual isopeptide and oxyester protein ubiquitylation activities of ARIH1 and set the stage for physiological investigations into this function of emerging importance.

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Catalysis of non-canonical protein ubiquitylation by the ARIH1 ubiquitin ligase

Purser,

Tripathi-Giesgen,

et al. 2023

Biochemical Journal

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HOIL1 mediates MDA5 activation through ubiquitination of LGP2

Cheng,

Zhu,

Liu

et al. 2024

Preprint

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The RIG-I-like receptors (RLRs), RIG-I and MDA5, are innate sensors of RNA virus infections that are critical for mounting a robust antiviral immune response. We have shown previously that HOIL1, a component of the Linear Ubiquitin Chain Assembly Complex (LUBAC), is essential for interferon (IFN) induction in response to viruses sensed by MDA5, but not for viruses sensed by RIG-I. LUBAC contains two unusual E3 ubiquitin ligases, HOIL1 and HOIP. HOIP generates methionine-1-linked polyubiquitin chains, whereas HOIL1 has recently been shown to conjugate ubiquitin onto serine and threonine residues. Here, we examined the differential requirement for HOIL1 and HOIP E3 ligase activities in RLR-mediated IFN induction. We determined that HOIL1 E3 ligase activity was critical for MDA5-dependent IFN induction, while HOIP E3 ligase activity played only a modest role in promoting IFN induction. HOIL1 E3 ligase promoted MDA5 oligomerization, its translocation to mitochondrial-associated membranes, and the formation of MAVS aggregates. We identified that HOIL1 can interact with and facilitate the ubiquitination of LGP2, a positive regulator of MDA5 oligomerization. In summary, our work identifies LGP2 ubiquitination by HOIL1 in facilitating the activation of MDA5 and the induction of a robust IFN response.

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Mechanistic insights into the enzymatic activity of E3 ligase HOIL-1L and its regulation by the linear ubiquitin chain binding

Cited by 2 publications

References 65 publications

Catalysis of non-canonical protein ubiquitylation by the ARIH1 ubiquitin ligase

Catalysis of non-canonical protein ubiquitylation by the ARIH1 ubiquitin ligase

HOIL1 mediates MDA5 activation through ubiquitination of LGP2

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