Autophagy-dependent secretion: mechanism, factors secreted, and disease implications

Abstract

Although best understood as a degradative pathway, recent evidence demonstrates pronounced involvement of the macroautophagic/autophagic molecular machinery in cellular secretion. With either overexpression or inhibition of autophagy mediators, dramatic alterations in the cellular secretory profile occur. This affects secretion of a plethora of factors ranging from cytokines, to granule contents, and even viral particles. Encompassing a wide range of secreted factors, autophagy-dependent secretion is implicated in diseases ranging from cancer to neurodegeneration. With a growing body of evidence shedding light onto the molecular mediators, this review delineates the molecular machinery involved in selective targeting of the autophagosome for either degradation or secretion. In addition, we summarize the current understanding of factors and cargo secreted through this unconventional route, and describe the implications of this pathway in both health and disease.

Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation

“…It has been reported that a wide range of stimuli can activate the NLRP3 inflammasome signaling pathway, which is involved in triggering autophagy-lysosomal dysfunction, and increase the release of proinflammatory factors in microglial cells [53]. Dupont et al demonstrated that autophagy is involved in mediating unconventional secretion of IL-1β [59][60][61]. In contrast, He et al proposed that the inflammasome itself might be one of the likely targets that is negatively controlled by autophagy [33].…”

Association between Porphyromonas gingivalis and tumor-promoting status in esophageal squamous cell carcinoma

“…PG, an important periodontal pathogen, has been reported to activate cellular autophagy, a possible mechanism in inflammatory disease. Multiple groups have observed that the secretion of IL6 depends upon autophagy in some cancers [32,33]. In vitro, when esophageal cancer cells were invaded by PG, autophagy was increased, as was IL-6 production.…”

Activation of the macroautophagy pathway byYersinia enterocoliticapromotes intracellular multiplication and egress of yersiniae from epithelial cells

“…Emerging evidence indeed indicates that autophagy-related events, in addition to their degradative functions, may participate in unconventional secretion processes, also described as "secretory autophagy" (Claude-Taupin et al, 2017;Ponpuak et al, 2015;Xu et al, 2018). Hence, autophagy can result in secretion of cytosolic proteins or release of sequestered material from cells (Claude-Taupin et al, 2017;New & Thomas, 2019). There exists substantial molecular and functional crosstalk between autophagy and exosome biogenesis (Cadwell & Debnath, 2018;Xu et al, 2018).…”

“…enterocolitica not only promotes intracellular survival but also egress of multiplying yersiniae from infected cells. Hence, autophagy can result in secretion of cytosolic proteins or release of sequestered material from cells(Claude-Taupin et al, 2017;New & Thomas, 2019). Liberation of the bacteria is obviously an active process because the fraction of released yersiniae in relation to the total pool of intracellular bacteria was significantly higher in autophagy-competent versus autophagyincompetent, FIP200-negative cells.…”

“…Yersinia replication. As autophagy-related pathways have been associated with secretory functions(Cadwell & Debnath, 2018;Claude-Taupin, Jia, Mudd, & Deretic, 2017;New & Thomas, 2019;Xu, Camfield, & Gorski, 2018), we determined whether autophagy…”