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

Figures & data

Figure 1. Initiating events in autophagy. The autophagic pathway centers around a convergence of 3 broad initiating events: 1) a catalytic cascade regulated by nutrient sensors, AMPK and MTORC1, leads to the phosphorylation of ULK1 and the subsequent activation of the BECN1 complex, which is essential for membrane nucleation and expansion; 2) the lipidation of LC3, which incorporates as LC3-II into the autophagic membrane; and 3) cargo recruitment by SQSTM1 or another autophagy cargo receptor, which bind primarily ubiquitinated (represented as ‘Ub’) cargo and traffic the cargo to the developing autophagic membrane.

Figure 2. Degradative events in autophagy. Autophagosome degradation centers around the fusion of the lysosome with the autophagosome. The pool of PtdIns3P surrounding the autophagosome recruits RAB7A. RAB7A facilitates binding of the autophagosome to the HOPS complex on the lysosome, and PLEKHM1 mediates this binding. As the membranes converge, a SNARE-mediated fusion event occurs between VAMP7 on the lysosome and STX17 on the autophagosome, with SNAP29 being recruited and acting as a Qab SNARE. This allows for fusion of the autophagosome and lysosome membranes and the degradation of autophagosome content.

Table 1. Secreted entities regulated by autophagy-dependent secretion.

Entity	Association with Autophagy	Species or Cell Type	Reference
Acb1	Atg1 mutant decreases secretion	P. pastoris	[20]
	Atg5 mutant decreases secretion	S. cerevisiae	[9]
	Vps30/Atg6 mutant decreases secretion	P. pastoris	[20]
	Atg7 mutant decreases secretion	S. cerevisiae	[9]
	Atg8 mutant decreases secretion	S. cerevisiae	[9]
	Atg9 mutant decreases secretion	P. pastoris	[20]
	Atg11 mutant decreases secretion	P. pastoris	[20]
	Atg12 mutant decreases secretion	S. cerevisiae	[9]
	Atg17 mutant decreases secretion	P. pastoris	[20]
	Nitrogen deficiency enhances secretion	S. cerevisiae; P. pastoris	[9,20]
	Rapamycin induces secretion	P. pastoris	[20]
IL1B	Starvation enhances secretion	Murine bone marrow-derived macrophages; human monocyte line, THP-1; human cervical cancer line, HeLa; human embryonic kidney cell line, HEK293T; MEFs	[4,27,29]
	ATG2 knockdown decreases secretion	HEK293T cells	[29]
	ATG4 mutant decreases secretion	HEK293T cells	[29]
	Atg5 knockout decreases secretion	Murine bone marrow-derived macrophages; MEFs	[27,29]
	ATG16L1 knockdown decreases secretion	THP-1	[4]
	Cells with low autophagic flux have less secretion of this factor compared to cells with greater autophagic flux	Human breast cancer cells	[3]
	BECN1 overexpression enhances secretion	Human breast cancer cells	[3]
	Colocalizes with LC3 in the cytoplasm	Murine bone marrow-derived macrophages	[27]
	Cofractionates with LC3 vesicles in sucrose gradient	HEK293T cells	[29]
	Bafilomycin A1 decreases secretion	Murine bone marrow-derived macrophages	[27]
	3-methyladenine and wortmannin decrease secretion	MEFs	[29]
IL6	ATG7 knockdown decreases secretion	Human pancreatic stellate cells; human breast cancer cells; human brain endothelial cells	[38,40,41]
	Atg7 knockout decreases secretion	Mouse brain	[41]
	BECN1 knockdown decreases secretion	Human head and neck cancer-associated fibroblasts; human breast cancer cells	[34,40]
	Associates with TASCC, which is inhibited by ATG5 knockdown	Human fibroblast line, IMR90; human promyelocytic leukemia line, HL60	[37]
CXCL8	BECN1 knockdown decreases secretion	Human head and neck cancer-associated fibroblasts	[34]
	Produced near TASCC, which is inhibited by ATG5 knockdown	HL60	[37]
	Cells with low autophagic flux have less secretion of this factor compared to cells with greater autophagic flux	Human breast cancer cells	[3]
	BECN1 overexpression enhances secretion	Human breast cancer cells	[3]
IL18	Bafilomycin A1 decreases secretion	Murine bone marrow-derived macrophages	[27]
	Atg5 knockout decreases secretion	Murine bone marrow-derived macrophages	[27]
HMGB1	Atg5 knockout decreases secretion	Murine bone marrow-derived macrophages	[27]
	ATG7 knockdown decreases secretion	Human glioblastoma cell line U87MG	[44]
	ATG12 knockdown decreases secretion	U87MG	[44]
ATP	ATG5 knockdown decreases secretion	Murine colon carcinoma line CT26; MEFs; Human osteosarcoma line U20S	[45, 46]
	Atg7 knockout and knockdown inhibits secretion	MEFs, U2OS	[46]
	ATG10 knockdown decreases secretion	U2OS	[46]
	BECN1 knockdown decreases secretion	U2OS	[46]
TGFB1	Ultrastructural colocalization with LC3 in double-membrane vesicles	Wi26 fibroblasts	[23]
	BECN1 knockdown decreases secretion	MEFs	[23]
	Atg5 knockout decreases secretion	MEFs	[23]
	ATG7 knockdown decreases secretion	MEFs, THP-1	[23]
	3-MA decreases secretion	MEFs, THP-1, murine primary macrophages	[23]
IDE (insulin degrading enzyme)	3-methyladenine decreases secretion	Mouse primary astrocytes	[56]
	Bafilomycin A1 decreases secretion	Mouse primary astrocytes	[56]
	Rapamycin induces secretion	Mouse primary astrocytes	[56]
	BECN1 knockdown decreases secretion	Mouse primary astrocytes	[55]
	ATG5 knockdown decreases secretion	Mouse primary astrocytes	[56]
	ATG7 mutant mice decrease secretion	Mouse brain	[56]
Amyloid beta	Atg7 knockout reduces cellular secretion	Mouse forebrain	[75]
	Rapamycin induces secretion	Mouse forebrain	[75]
	Spautin-1 inhibits secretion	Mouse forebrain	[75]
SNCA	ATG5 knockdown decreases secretion	Rat pheochromocytoma cell line, PC12	[77]
	3-MA inhibits secretion	PC12	[77]
Secretory Granules
Paneth cell contents (LYZ [lysozyme])	Dysregulated and reduced LYZ exocytosis from Atg5 knockout	Mouse intestinal crypt	[48]
	Dysregulated and reduced lysozyme exocytosis from ATG16L1 mutant	Mouse intestinal crypt	[48,49]
Weibel-Palade bodies	ATG5 knockdown decreases secretion	Human primary endothelial cells	[50]
	ATG7 knockdown decreases secretion	Human primary endothelial cells	[50]
Secretory lysosomes	ATG4B or LC3 mutant decreases secretion	Murine osteoclasts	[51]
	Atg5 knockout decreases secretion	Murine osteoclasts	[51]
	Atg7 knockout decreases secretion	Murine osteoclasts and bone marrow-derived mast cells	[51,53]
Reflect Autophagy Dynamics
LIF, FAM3C, DKK3	Cells with low autophagic flux have less secretion of these factors compared to cells with greater autophagic flux	Human breast cancer cells	[3]
	BECN1 overexpression enhances secretion	Human breast cancer cells	[3]
Viruses
Poliovirus	BECN1 knockdown decreases extracellular viral titer; whereas overexpression increases viral titer	HeLa cells with poliovirus infection	[64]
	LC3 knockdown decreases extracellular viral titer	HeLa cells with poliovirus infection	[5,64]
	ATG12 knockdown decreases extracellular viral titer	HeLa cells with poliovirus infection	[5]
	Rapamycin increases extracellular titer	HeLa cells with poliovirus infection	[5]
	3-MA treatment inhibits secretion	HeLa cells with poliovirus infection	[5]
	Colocalizes with LC3^+ vesicle	HeLa cells with poliovirus infection	[64]
Rhinovirus	LC3^+ membrane associated	HeLa cells with rhinovirus infection	[5]
Coxsackie virus	LC3^+ membrane associated	HeLa cells with coxsackie virus infection	[5]
Dengue virus	Spautin-1 decreases viral yield	Baby hamster kidney cell line BHK-21, and HeLa cells with dengue virus	[67]
Mycobacteria	Atg1 knockdown decreases bacterial ejection	Dictyostelium	[72]
	Atg6A knockdown decreases bacterial ejection	Dictyostelium	[72]
	Atg7 knockdown decreases bacterial ejection	Dictyostelium	[72]

Figure 3. Markers of degradative and secretory autophagosomes. Trafficking of the autophagosome depends on the proteins decorating the outer membrane. Both degradative and secretory routes are labeled with LC3. STX17 directs fusion of the degradative autophagosome with the lysosome. SEC22B and TRIM16 direct an autophagosome for secretion.

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