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The autophagy-related 12 (ATG12)–autophagy-related 5 (ATG5)–autophagy-related 16-like 1 (ATG16L1) ternary complex forms a dimer that facilitates the translocation of autophagy-related 8 (ATG8) proteins from autophagy-related 3 (ATG3) to phosphatidylethanolamine (PE). This event is fundamental for cargo sequestration and autophagy progression. Thus, one possible strategy for inhibiting autophagy is to disrupt the critical ATG5-ATG16L1 interaction during this process. So far very few known specific autophagy modulators can block autophagy effectively. We recently discovered a small-molecule compound, T1742, which is able to block the ATG5-ATG16L1 and ATG5-TECAIR interactions in vitro at the low-micromolar range (IC50 = 1~2 μM). Flow cytometry assay and western blot experiments indicated that T1742 can also effectively inhibit autophagy in living cells in a dose-dependent manner. To the best of our knowledge, T1742 represents the first small-molecule autophagy inhibitor that disrupts the protein-protein interactions involving ATG5. Such compounds may serve as a new chemical tool for deciphering the mechanism of autophagy or a potential candidate for therapeutic application.

Summary: Autophagy is a dynamic process of subcellular degradation, which has recently sparked great interest because it is involved in various developmental processes and various diseases including cancer. Autophagy-related 16-like 1 is a component of a large protein complex essential for autophagosome formation. We previously applied proteomic methods to characterize differentially expressed proteins in oral squamous cell carcinoma cells and detected significantly high expression levels of autophagy-related 16-like 1 in oral squamous cell carcinoma–derived cell lines compared to human normal oral keratinocytes. In the current study, to further determine the potential involvement of autophagy-related 16-like 1 in oral squamous cell carcinoma, we evaluated the state of autophagy-related 16-like 1 protein expression in human oral premalignant lesions and primary oral squamous cell carcinomas, and correlated the results with clinicopathologic variables. Autophagy-related 16-like 1 immunoreaction was predominant in a variety of subcellular components of oral squamous cell carcinoma tissues, including the cytoplasm and plasma membrane of malignant cells (45% and 39%, respectively) and peritumoral and intratumoral stroma (52%), whereas all of the components in normal tissues had no or faint autophagy-related 16-like 1 expression. In addition, high stromal expression of autophagy-related 16-like 1 was associated significantly with lymphovascular invasion of tumor cells (P = .037) and positive lymph node status (P = .015). Furthermore, cytoplasmic and plasma membranous autophagy-related 16-like 1 were also expressed in abundance in the oral premalignant lesion cells (74% and 32%, respectively). Our finding suggests that dysregulation of autophagy-related 16-like 1 protein expression is a frequent and early event during oral carcinogenesis and could affect the malignant behavior of oral squamous cell carcinoma cells. [Copyright &y& Elsevier]

Esophageal achalasia is characterized by abnormal peristalsis of the esophageal body and impaired relaxation of the lower esophageal sphincter (LES); however, its etiology remains unknown. One of the potential causes of esophageal achalasia is herpes simplex virus type 1 (HSV-1). Following infection with HSV-1, a complex interaction between the autoimmune and inflammatory responses is initiated. Viral microRNAs (miRNAs/miRs) serve a crucial role in this interaction. In the present study, the expression of E3 ubiquitin-protein ligase component n-recognition 1 ( UBR1 ) and autophagy-related 16-like 1 ( ATG16L1 ) was assessed in patients with sporadic and classic achalasia as potential targets of the viral miRNAs. We assessed the mRNA levels of target transcripts using reverse transcription-quantitative PCR. UBR1 expression was slightly decreased, although the difference was not significant. However, ATG16L1 expression was significantly decreased in the LES. In conclusion, ATG16L1 expression was reduced in the LES of achalasia patients; therefore, ATG16L1 might be a target of HSV1-miR-H1, and its reduction could be related to the disease mechanism., (Copyright © 2020, Spandidos Publications.)