Autophagy and Its Role in Protein Secretion: Implications for Cancer Therapy

Table 1

Proteins whose secretion is known to be regulated by autophagy. The table shows proteins whose secretion has been shown to be regulated by alterations in the autophagic pathway, the methods used to manipulate autophagy, and the effect of autophagy on secretion: positive, if autophagy inhibition impairs secretion, or negative, if autophagy inhibition increased secretion (3MA: 3-methyl adenine; LPS: lipopolysaccharide; CQ: chloroquine; kd: knockdown; Baf: bafilomycin A1; EMT: epithelial to mesenchymal transition).

Secreted protein	Protein function	Method(s) used to modulate autophagy	Autophagy’s effect on secretion	Ref.
Acb1	Acyl-CoA-binding protein involved in yeast sporulation	ATG1, 5, 6, 7, 8, 9, 12, 17 and VAM7 mutant yeast; rapamycin	Positive; genetic inhibition of autophagy decreased and rapamycin increased secretion. Fusion of the autophagosome with the vacuole was not related to secretion.	[67, 68]
Amyloid-β peptide	Element of the amyloid plaques involved in Alzheimer’s disease	Atg7^−/−	Positive; genetic inhibition of autophagy caused intracellular Ab accumulation and reduced amyloid B peptide secretion.	[72]
Annexin A1	Regulator of the inflammatory process	Beclin1 kd, 3MA, and Atg5^−/−	Positive; genetic inhibition of autophagy or 3MA treatment decreased secretion induced by inflammasome activators. Found in screening experiments of secreted proteins regulated by autophagy.	[66, 70, 108]
Annexin A2	Ca^2+-dependent phospholipid-binding protein	ATG5 kd, 3MA, and lysosomal inhibitors	Positive; genetic inhibition of autophagy or 3MA treatment decreased secretion in IFN-γ-stimulated lung epithelial cells. Found in screening experiments of secreted proteins regulated by autophagy.	[70, 86]
α-Synuclein	Aggregation-prone protein involved in Parkinson’s disease	ATG5 kd, TPPP/p25 which impaired autophagic flux at the lysosomal fusion step, trehalose, and lysosomal inhibitors	Positive; autophagy inhibition in the presence of TPP/p25 decreased secretion. Autophagosome-lysosome fusion impairment was necessary for secretion, and autophagosome-lysosome fusion impairment enhanced secretion of an LC3/p62^+ vesicle.	[69, 70]
β-Hexosaminidase	Lysosomal enzyme, indicator of mast cell degranulation	Atg7^−/− and Atg12 kd	Positive; genetic inhibition of autophagy decreased mast cell degranulation.	[75]
Cathepsin D	Lysosomal protease	Beclin1 kd, 3MA, and Atg5^−/−	Positive; genetic inhibition of autophagy or 3MA treatment decreased secretion induced by inflammasome activators. Found in screening experiments of secreted proteins regulated by autophagy.	[66, 108]
Cathepsin K	Bone resorption	Atg5^−/−, Atg7^−/−, and Atg4^C74A dominant negative	Positive; autophagy inhibition decreased secretory lysosome delivery to the plasma membrane.	[74]
CXCL8	Chemokine produced by macrophages and epithelial cells	ATG7 kd	Positive; autophagy inhibition decreased secretion.	[100]
DKK3	Glycoprotein with angiogenesis and invasiveness-promoting roles	ATG7 kd	Positive; autophagy inhibition decreased secretion.	[100]
FAM3C	Secreted protein inducer of EMT	ATG7 kd	Positive; autophagy inhibition decreased secretion.	[100]
Ferritin	Iron storage protein	LC3B kd	Positive; inhibition of autophagy decreased secretion in response to lysosomal damage.	[66]
Galectin 3	Lectin with affinity for β-galactoside glycoconjugates	Beclin1 kd and 3MA	Positive; genetic inhibition of autophagy or 3MA treatment decreased secretion induced by inflammasome activators.	[108]
Histamine	Inflammatory response, component of mast cell granules	Atg7−/− and Atg12 kd	Positive; genetic inhibition of autophagy decreased mast cell degranulation.	[75]
HMGB1	Alarmin normally present in the nucleus and released during cell death	ATG5, 7, and 12 kd	Positive; genetic inhibition of autophagy decreased secretion in cancer cells treated with targeted therapy.	[93]
IL-1β	Inflammatory response	Atg5^−/−, bafilomycin A [64], beclin 1 kd, 3MA [108], ATG16L1, LC3B kd [66], and Atg7^−/− [91]	Positive; genetic [64] or pharmacological [108] inhibition of autophagy decreased secretion in response to inflammasome activation, lysosomal damage [66], or UVB irradiation [91].	[64, 66, 91, 108]
		Truncated Atg16L1, Atg7^−/−, and 3MA [63, 77], Map1lc3b^−/− or becn1^−/− [76], and becn1 kd [77]	Negative; genetic autophagy inhibition or PI3K inhibitor treatment induced secretion in LPS primed macrophages.	[63, 76, 77]
IL-6	Inflammation	ATG5, ATG7, ATG12, beclin1 kd, and Atg7^−/−	Positive; genetic inhibition of autophagy decreased secretion in cancer cell lines [40, 57, 89], in UVB irradiated skin [91], or in hepatitis virus infected hepatocytes [109].	[40, 57, 89, 91, 109]
		ATG7 and Beclin1 kd	Negative; genetic inhibition of autophagy increased secretion in a breast cancer cell line but not others.	[40]
IL-8	Chemotactic factor and neutrophil activator	ATG5 and ATG7 kd	Positive; genetic inhibition of autophagy decreased secretion in cancer cell lines [100] or in hepatitis virus-infected hepatocytes [109].	[100, 109]
IL-18	Proinflammatory cytokine	Truncated ATG16L1 [63] and Map1lc3b^−/− or Becn1^−/− [76]	Negative; genetic autophagy inhibition induced secretion in mouse models of colitis or sepsis or in LPS-primed macrophages.	[63, 76]
		3MA or bafilomycin treatment	Positive; pharmacological inhibition of both initial and degradation phases of autophagy decreased secretion in allergen-induced IL-18 secretion.	[110]
LIF	Cytokine involved in hematopoietic differentiation, stem cell development, metabolism, and growth promotion	ATG7 kd	Positive; autophagy inhibition decreased secretion.	[100]
Lysozyme	Antimicrobial protein	Hypomorphic ATG16L1, Atg5^−/− [61] and Atg16L1^T300A, 3MA, and CQ [62]	Positive; lysozyme secretion was impaired from Paneth cells by genetic inhibition of Atg genes or 3MA but not CQ treatment.	[61, 62]
Metalloproteinase 2/9	Extracellular matrix-degrading proteases	ATG7 and 12 kd	Positive; genetic inhibition of autophagy decreased secretion.	[57]
MIF	Proinflammatory cytokine	Atg5 kd, atg7^−/−, and 3MA treatment	Negative; inhibition of autophagy increased MIF secretion in LPS-stimulated macrophages.	[80]
Neuropeptide Y	Neurotransmitter	Atg16L1 kd	Positive; Atg16L1 kd but not Atg13 or ULK1 kd decreased secretion in neuroendocrine cells.	[111]