Chymotrypsin B2 (CTRB2) Deletion Variant Induces Endoplasmic Reticulum Stress but does not Increase Risk for Chronic...

CTRB2-del, a commonly occurring loss-of-function deletion variant in the CTRB2 gene encoding chymotrypsinogen B2 was shown to induce endoplasmic reticulum (ER) stress and increase risk for pancreatic cancer but not for chronic pancreatitis (CP). Since other digestive enzyme variants that cause misfolding and induce ER stress are strong risk factors for CP, the lack of association between CP and the CTRB2-del variant is surprising. The aim of the present study was to re-examine the biochemical and clinical characteristics of the CTRB2-del variant.

We performed experiments with AR42J cells transduced with adenoviral vectors and investigated disease association in Hungarian and German cohorts of CP cases.

We found that the CTRB2-del protein was not secreted from AR42J cells but accumulated inside and induced significant ER stress. Curiously, epitope tagging CTRB2-del with a polyhistidine tail abolished its capacity to elicit ER stress even though the tagged construct remained defective in secretion and was retained intracellularly. Human genetic studies demonstrated similar carrier frequency of the CTRB2-del variant in CP cases and controls.

We replicated the ER-stress causing effect of the CTRB2-del variant and confirmed the lack of association with CP. The observations also revealed that epitope-tagging may alter the cellular effects of the CTRB2-del protein. The lack of association between ER stress and CP risk in carriers of the CTRB2-del variant raises the possibility that ER stress is a marker of digestive enzyme misfolding but does not drive CP onset and/or progression.