The autophagic machinery ensures nonlytic transmission of mycobacteria

Abstract

In contrast to mechanisms mediating uptake of intracellular bacterial pathogens, bacterial egress and cell-to-cell transmission are poorly understood. Previously, we showed that the transmission of pathogenic mycobacteria between phagocytic cells also depends on nonlytic ejection through an F-actin based structure, called the ejectosome. How the host cell maintains integrity of its plasma membrane during the ejection process was unknown. Here, we reveal an unexpected function for the autophagic machinery in nonlytic spreading of bacteria. We show that ejecting mycobacteria are escorted by a distinct polar autophagocytic vacuole. If autophagy is impaired, cell-to-cell transmission is inhibited, the host plasma membrane becomes compromised and the host cells die. These findings highlight a previously unidentified, highly ordered interaction between bacteria and the autophagic pathway and might represent the ancient way to ensure nonlytic egress of bacteria.autophagy | Dictyostelium discoideum | Mycobacterium marinum | ejection

Secretory autophagy

“…In addition, the involvement of other well-known autophagy receptors (e.g. p62, NBR1, NDP52, and optineurin), which facilitate the delivery of ubiquitinated autophagic substrates to degradative autophagosomes, remains unexplored, with the exception of SQSTM1 (the p62 Dictyostelium ortholog), which turned out to be present during but functionally dispensable for secretion of a particulate substrate termed ejectosome [21]. In addition to these well-known autophagy receptors, the tripartite motif (TRIM) family of proteins has been recently reported as a new class of dual autophagic receptor—regulators [40] and it is possible that at least some member(s) of this protein family may act in secretory autophagy.…”

“…Intracellular pathogens such as bacteria [21, 51] and viruses [16, 52–54] can be released from infected cells in a variety of process assisted by the autophagic machinery (Table 1, I-D). A recent study with Mycobacterium marinum [21] showed that autophagosomal organelles chaperone a structure termed the ejectosome [55], an actin-tail based apparatus enabling cytosolic bacteria to exit the host cell with the purpose of potentially contributing to microbial cell-to-cell spread (Fig.…”

“…A recent study with Mycobacterium marinum [21] showed that autophagosomal organelles chaperone a structure termed the ejectosome [55], an actin-tail based apparatus enabling cytosolic bacteria to exit the host cell with the purpose of potentially contributing to microbial cell-to-cell spread (Fig. 2).…”

“…2). A functional (non-lytic to the host cell) ejectosome in M. marinum -infected amoeba Dictyostelium is seen [21] as escorted by a distinct polar autophagic profile, which is Atg8 positive, ubiquitin-positive, and SQSTSM1 (an autophagic receptor)-positive. Although the host-sparing function of the ejectosome was SQSTM1-independent (thus indicating possible involvement of other unknown receptors) it was Atg5, Atg7 and Atg6 (Beclin)-dependent.…”

“…In contrast to degradative autophagy, it has become slowly but increasingly apparent that autophagy has other, sometimes biogenesis-associated functions as well as a role in unconventional secretion (secretory autophagy; Figure 2). Secretory autophagy exports a range of cytoplasmic substrates (Table 1) [2, 12–19] [20, 21]. This review primarily examines the developing concept of secretory autophagy including its cargo, biological functions, and the currently limited understanding of its regulation.…”