Bacterial antiviral defense pathways encode eukaryotic-like ubiquitination systems

Lydia R. Chambers, Qiaozhen Ye, Jiaxi Cai, Minheng Gong, Hannah E. Ledvina, Huilin Zhou, Aaron T. Whiteley, Raymond T. Suhandynata, Kevin D. Corbett
2023 · doi:10.1101/2023.09.26.559546
preprint OA: closed CC-BY-NC-ND-4.0
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Abstract

Ubiquitination and related pathways play crucial roles in protein homeostasis, signaling, and innate immunity 1-3 . In these pathways, an enzymatic cascade of E1, E2, and E3 proteins conjugates ubiquitin or a ubiquitin-like protein (Ubl) to targetprotein lysine residues 4 . Bacteria encode ancient relatives of E1 and Ubl proteins involved in sulfur metabolism 5,6 but these proteins do not mediate Ubl-target conjugation, leaving open the question of whether bacteria can perform ubiquitination-like protein conjugation. Here, we demonstrate that a bacterial antiviral immune system encodes a complete ubiquitination pathway. Two structures of a bacterial E1:E2:Ubl complex reveal striking architectural parallels with canonical eukaryotic ubiquitination machinery. The bacterial E1 encodes an N-terminal inactive adenylation domain (IAD) and a C-terminal active adenylation domain (AAD) with a mobile α-helical insertion containing the catalytic cysteine (CYS domain). One structure reveals a pre-reaction state with the bacterial Ubl C-terminus positioned for adenylation, and the E1 CYS domain poised nearby for thioester formation. A second structure mimics an E1-to-E2 transthioesterification state, with the E1 CYS domain rotated outward and its catalytic cysteine adjacent to the bound E2. We show that a deubiquitinase (DUB) in the same pathway pre-processes the bacterial Ubl, exposing its C-terminal glycine for adenylation. Finally, we show that the bacterial E1 and E2 collaborate to conjugate Ubl to target-protein lysine residues. Together, these data reveal that bacteria possess bona fide ubiquitination systems with strong mechanistic and architectural parallels to canonical eukaryotic ubiquitination pathways, suggesting that these pathways arose first in bacteria.

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License: CC-BY-NC-ND-4.0