Numerous bacterial pathogens have evolved tactics to interfere with the host ubiquitination network to evade clearance by the innate immune system. Nevertheless, the subtle antagonism between a bacterial ubiquitinase and a host deubiquitinase, through which they modify their respective targets within a multifaceted network, has yet to be characterized. BRCC3 isopeptidase complex (BRISC) is a newly identified K63-specific deubiquitinase complex that plays a crucial role in cellular signaling pathways such as inflammation. NleG, a type III secretion system (T3SS) effector, contains a conserved RING E3 ubiquitin ligase domain that interacts with host ubiquitination machinery, along with a distinct substrate-recognition domain that targets host proteins. Here, one particular variant, NleG6, was identified as mediating K27- and K29-linked polyubiquitination at residues K89 and K114 of ABRAXAS2/FAM175B, a scaffolding protein within the BRISC complex, leading to its degradation through TOLLIP (toll interacting protein)-mediated selective autophagy. Further investigations elucidated that ABRAXAS2 degradation triggered the subsequent degradation of adjacent BRCC3, which in turn, hindered TNIP1/ABIN1 degradation, ultimately inhibiting NFKB/NF-κB (nuclear factor kappa B)-mediated inflammatory responses. This chain of events offers valuable insights into the NFKB activation by the K63-specific deubiquitinating role of BRISC, unveiling how bacteria manipulate ubiquitin regulation and selective autophagy within the BRISC network to inhibit the host's inflammatory response and thus dominate a pathogen-host tug-of-war.