Atg9 is the only essential transmembrane protein involved in cellular autophagy. Autophagy regulates cellular homeostasis by allowing the turnover and recycling of misfolded proteins and damaged organelles. Formation of the double-membrane isolation membrane that forms the pre-autophagosome requires the contribution of highly mobile cytoplasmic vesicles containing Atg9. These vesicles are derived from recycling endosomes and are responsible for recruiting and delivering lipid components to the assembling autophagosome. Given this essential role in autophagosome assembly Atg9 is an excellent marker for the induction of autophagy and tracking membrane sources for formation of the autophagosome. In vertebrates Atg9 exists in two different isoforms: Atg9a and Atg9b. Atg9a is ubiquitously expressed while Atg9b is enriched in the placenta and the pituitary (1) and is induced by hypoxic conditions (2). Both proteins show similar localization in cytoplasmic vesicles and in early autophagosome structures. However the lack of autophagosomes in placenta tissue may indicate an alternative role in membrane trafficking apart from autophagy. While the differences between these two isoforms remain unknown, Atg9b is able to functionally complement Atg9a during autophagy. Given these data Atg9b may have tissue-specific functions during membrane trafficking and autophagy induction in vertebrates.
The FDA used a mouse model of pancreatitis in an effort to identify potential biomarkers for the difficult to diagnose condition of drug-induced pancreatitis (3). They used various antibodies targeting markers of autophagy and pancreatic stress, including the Atg9b antibody, in an attempt to identify potential biomarkers specific for pancreatitis. The Atg9b antibody was generated using a unique a peptide corresponding to the unique C-terminal region of the protein in order to distinguish between closely related isoforms. Immunohistochemistry with the Atg9b antibody showed localization to autophagosomes but showed only a minimal increase in expression upon induction of pancreatitis. Their study demonstrated the ability to use Atg9a and Atg9b antibodies to examine Atg9 isoforms as autophagy markers in rodent cells however, although Atg9b and Atg9a both localized to autophagosomes the researchers were unable to confirm a functional role for either protein in pancreatitis. Further research using Atg9a and Atg9b antibodies is needed to clarify the role of these protein isoforms in various vertebrate tissues, including the placenta, and under varying oxygen levels.
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