We recently learned that the cDNA encoding CEL purchased from OpenBiosystems (clone ID 5187959; GenBank™ accession no. BC042510.1) for this work contains a three-base pair inframe deletion resulting in p.E365del. (The correct sequence should be 356NKGNKKVTEEDFYKLVSEFTITKGL380 and not 356NKGNKKVTE-DFYKLVSEFTITKGL380.) p.E365 is conserved in most primates. The residue is located in a surface loop of the CEL globular domain distant from the catalytic site and the bile acid-binding site. In our study, both CEL14R and CEL MODY contained p.E365del. The experimental variable was the sequence of the variable number of tandem repeat (VNTR) domain (Fig. 1A). Thus, the reported differences between CEL14R and CEL MODY reflect the effect of the VNTR MODY mutation on CEL folding. In support of this contention, another group that expressed a form of CEL with p.E365 also found that CEL MODY forms significant levels of intracellular protein aggregates compared with CEL14R (Johansson, B. B., Torsvik, J., Bjørkhaug, L., Vesterhus, M., Ragvin, A., Tjora, E., Fjeld, K., Hoem, D., Johansson, S., Ræder, H., Lindquist, S., Hernell, O., Cnop, M., Saraste, J., Flatmark, T., Molven, A., and Njølstad, P. R. (2011) Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl ester lipase gene-maturity onset diabetes of the young (CEL-MODY): A protein misfolding disease. J. Biol. Chem. 286, 34593-34605). Because our hypothesis was that CEL MODY causes disease by misfolding and activating maladaptive cell signaling pathways, the presence of p.E365del raises concerns that deletion may have affected protein folding efficiency and contributed to the unfolded protein response we observed in our study. Based on our results with CEL14R, the effect of p.E365del on the folding of CEL appears minimal. CEL14R was robustly secreted and only formed low levels of detergent-insoluble intracellular aggregates (Figs. 2 and 5). CEL14R had good activity against triglycerides (Fig. 1) and was stimulated by bile acids (Xiao, X., and Lowe, M. E., unpublished observations). The results with CEL14R also showed that the presence of p.E365del was not sufficient to trigger activation of cell death and inflammatory pathways to the same level as seen with CEL MODY (Figs. 4 and 7). Still, we cannot exclude the possibility that the presence of p.E365del amplified the unfolded protein response elicited by the aggregation of CEL MODY resulting in a more robust activation of cell death pathways. Given this new information, the conclusion that "a mutation in CEL is sufficient to cause ER stress, induction of the UPR, NF-κB activation, and acinar cell death" in the first sentence of the last paragraph under "Discussion" is overstated. Even with this caveat, our data support the conclusion that disorders of protein homeostasis can have a role in the pathophysiology of chronic pancreatitis.