Antibody- and TRIM21-dependent intracellular restriction ofSalmonella enterica

Abstract

TRIM21 ('tripartite motif-containing protein 21', Ro52) is a ubiquitously expressed cytosolic Fc receptor, which has a potent role in protective immunity against nonenveloped viruses. TRIM21 mediates intracellular neutralisation of antibody-coated viruses, a process called ADIN (antibody-dependent intracellular neutralisation). Our results reveal a similar mechanism to fight bacterial infections. TRIM21 is recruited to the intracellular pathogen Salmonella enterica in epithelial cells early in infection. TRIM21 does not bind directly to S. enterica, but to antibodies opsonising it. Most importantly, bacterial restriction is dependent on TRIM21 as well as on the opsonisation state of the bacteria. Finally, Salmonella and TRIM21 colocalise with the autophagosomal marker LC3, and intracellular defence is enhanced in starved cells suggesting an involvement of the autophagocytic pathway. Our data extend the protective role of TRIM21 from viruses to bacteria and thereby strengthening the general role of ADIN in cellular immunity.

Antibody-antigen kinetics constrain intracellular humoral immunity

“…Simultaneous with this degradation process, K63 ubiquitin chains released from TRIM21 by the 19S-associated deubiquitinase Poh1 stimulate NFκB, AP-1 and IRF3 immune transcription pathways, leading to potent activation of pro-inflammatory immunity56. TRIM21 antiviral activities have been demonstrated during infection by non-enveloped viruses from diverse families including adenoviridae, caliciviridae and picornaviridae and the intracellular bacteria Salmonella678. TRIM21 function provides an important component of protective antibody immunity in vivo .…”

Precision autophagy directed by receptor regulators – emerging examples within the TRIM family

“…As a consequence, Rhesus TRIM5, but not human TRIM5, contributes to defense against HIV-1 through precision autophagy. Antimicrobial roles of TRIMs that are mediated through autophagy might extend to a defense against other intracellular pathogens; this includes bacteria (Rakebrandt et al, 2014) and possibly fungi. For instance, the antifungal activity of TRIM62 that is conveyed by CARD9, a mediator of innate immunity signals, which although not yet formally linked to autophagy (Cao et al, 2015), is known to play a role in autophagy through the interactions it has with RUBICON (encoded by KIAA0226) (Yang et al, 2012).…”

“…TRIMs are involved in a variety of seemingly disparate cellular processes (Table S1); these include cell survival and death (Grignani et al, 1993), cell cycle and differentiation (Wang et al, 1998), metabolic states (Skurat et al, 2002), cell membrane repair (Cai et al, 2009), synaptic vesicle exocytosis (Li et al, 2001), senescence (Pearson et al, 2000), stem cell pluripotency (Sato et al, 2012) and erythrocyte differentiation (Blaybel et al, 2008;Barde et al, 2013), as well as the control of viral, bacterial and fungal infections (Nisole et al, 2005;Rakebrandt et al, 2014;Cao et al, 2015). These and additional roles are linked to a variety of health conditions.…”

A re-evaluation of the role of B cells in protective immunity to Chlamydia infection

“…Alternatively, rather than provide a killing mechanism extra-cellularly, it is possible that some antibodies can find their way inside infected cells. Recent discovery of intracellular Fc receptor, TRIM21 has suggested an intracellular defending mechanism for antibody-mediated protection to viral and bacteria infections [71,72]. …”