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

Area of Science:

• Biochemistry
• Genetics
• Gastroenterology

Background:

• The CTRB2-del variant, a loss-of-function deletion in the CTRB2 gene, induces endoplasmic reticulum (ER) stress.
• This variant increases pancreatic cancer risk but lacks association with chronic pancreatitis (CP), which is unexpected given other ER stress-inducing digestive enzyme variants are CP risk factors.

Purpose of the Study:

• To re-examine the biochemical and clinical characteristics of the CTRB2-del variant.
• To investigate the surprising lack of association between CTRB2-del and chronic pancreatitis.

Main Methods:

• Experiments were conducted using AR42J cells transduced with adenoviral vectors.
• Disease association was investigated in Hungarian and German cohorts of chronic pancreatitis (CP) cases.

Main Results:

• CTRB2-del protein accumulated intracellularly and induced significant ER stress in AR42J cells, with impaired secretion.
• Epitope tagging of CTRB2-del abolished ER stress induction, despite continued intracellular retention and defective secretion.
• Human genetic studies showed no significant difference in CTRB2-del carrier frequency between CP cases and controls.

Conclusions:

• The ER-stress-inducing effect of CTRB2-del was confirmed, along with its lack of association with CP.
• Epitope-tagging can alter the cellular impact of the CTRB2-del protein.
• The dissociation of ER stress and CP risk suggests ER stress may be a marker, not a driver, of CP onset or progression.