Cytosol-dwelling bacteria engage in a ubiquitination race to avoid antibacterial autophagy

One of the defense mechanisms of host cells against bacterial pathogens is antibacterial macroautophagy/autophagy that relies on ubiquitination of a pathogen for recognition by specific receptors that deliver the pathogen to phagophores. RNF213 is an E3 ligase that mediates ubiquitination of lipopolysaccharides (LPS) on bacteria dwelling in the host cytosol. However, one type of cytosol-invading bacteria, <i>Shigella flexneri</i>, evolved a mechanism through which it can avoid LPS ubiquitination. <i>S. flexneri</i> employs IpaH1.4, an effector protein with E3 ligase activity that ubiquitinates RNF213 for proteasomal degradation. Here, we discuss a study that discovered this <i>S. flexneri</i> strategy, and revealed by cryo-EM that the IpaH1.4 leucine-rich repeat recognizes and binds the RNF213 RING domain. The mass spectrometry data showed that IpaH1.4 targets several other RING-containing E3 ligases implicated in inflammation and immunity, which opens a new field for xenophagy.<b>Abbreviations</b>: cryo-EM, cryo-electron microscopy; LPS, lipopolysaccharide; LRR, leucine-rich repeat; LUBAC, linear ubiquitin chain assembly complex; NEL, novel E3 ligase; OPTN, optineurin.