Bag it, tag it: ubiquitin ligases and host resistance to Mycobacterium tuberculosis

Abstract

Infection with Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), remains a significant global epidemic. Host resistance to Mtb depends on both adaptive and innate immunity mechanisms, including development of antigen-specific CD4 and CD8 T cells, production of inflammatory cytokines, bacterial phagocytosis and destruction within phagolysosomes, host cell apoptosis, and autophagy. A key regulatory mechanism in innate immunity is the attachment of the small protein ubiquitin to protein and lipid targets by the enzymatic activity of ubiquitin ligases. Here, we summarize the latest advances on the role of ubiquitination and ubiquitin ligases in host immunity against Mtb, with a focus on innate immunity signaling, inflammation, and antimicrobial autophagy. Understanding how ubiquitin ligases mediate immunity to Mtb, and the specific substrates of distinct ubiquitin ligases in the context of Mtb infection, could facilitate development of new host-directed antimicrobials.

Keywords: immune response; infectious diseases; tuberculosis; ubiquitin ligase; ubiquitination.

Figure 1:. Ubiquitin ligase TRIM27 regulates MAPK signaling and apoptosis in macrophages infected with mycobacteria.

Upon mycobacterial infection, TRIM27 ubiquitinates a yet to-be-identified substrate and facilitates JNK/p38 MAPK signaling (1) in a mechanism dependent on its RING domain, which leads to secretion of proinflammatory cytokines IL-1beta and IL-18. Additionally, TRIM27 may promote caspase 3-dependent apoptotic cell death (2). Overall, these effects of TRIM27 in macrophages result in intracellular mycobacterial killing and control of infection (3). To overcome these mechanisms, mycobacteria may secrete PtpA, which interacts with the TRIM27 RING domain possibly disrupting TRIM27 interaction with its substrate (4), leading to inhibition of TRIM27 antimycobacterial activity.

Figure 2:. Ubiquitin ligase ANAPC2 inhibits inflammation during Mtb infection.

Host ANAPC2 mediates K11-linked polyubiquitination of the Mtb secreted protein Rv0222 (1), which is required for the recruitment of the tyrosine phosphatase SHP1 to TRAF6 adaptor (2). Interaction between SHP1 and TRAF6 leads to decreased activation of NF-κB and AP-1 transcription factors (3), and reduced production of the proinflammatory cytokines IL-1 and IL-6.

Figure 3:. Ubiquitin ligase LNX1 regulates macrophage apoptosis and resistance to Mtb by targeting NEK6 for degradation.

During Mtb infection, LNX1 targets NEK6 with K48-linked polyubiquitin and directs it for proteasomal degradation (1). NEK6 is a protein kinase that promotes STAT3 phosphorylation (2), which leads to inhibition of macrophage apoptosis and consequent facilitation of intracellular Mtb replication (3). Degradation of NEK6 by LNX1 represents an important antimycobacterial mechanism since it favors apoptotic cell death of Mtb-infected macrophages and control of mycobacterial replication. To circumvent the antimycobacterial effect of LNX1, Mtb induces the expression of miR-325–3p (4), which targets LNX1 mRNA for degradation leading to accumulation of NEK6 and subsequent inhibition of apoptosis, impairing mycobacterial clearance by macrophages.

Figure 4:. Ubiquitin ligases Parkin and Smurf1 mediates ubiquitin-dependent xenophagy of Mtb.

During Mtb infection of macrophages, Mtb-containing vacuoles are target by Parkin with K63-linked polyubiquitin, which is required for specific recruitment of the autophagy adaptors NBR1, NDP52, pTBK1, and p62 to Mtb vacuoles (1). Concomitantly, Smurf1 targets Mtb vacuoles with K48-linked polyubiquitin which is required for specific recruitment of the proteasome to Mtb-containing vacuoles (2). Parkin- and Smurf1-dependent recruitment of these adaptors is essential to deliver Mtb vacuoles to autophagosomes (3), followed by autophagosome maturation, fusion with lysosomes and autophagic elimination of Mtb (4). The function of Smurf1-dependent proteasome recruitment to Mtb phagosomes in antimycobacterial autophagy is unknown.