Misfolded HLA class I accumulation in the endoplasmic reticulum induces the cell surface expression of high mannose glycoforms via a Golgi-mediated secretory route 3608

Abstract Description HLA class I assembly with peptides largely depends on the transporter associated with antigen processing (TAP) as a peptide source. However, many TAP-deficient cells display suboptimally assembled cell surface HLA class I molecules bearing immature (high mannose) glycans. Endoplasmic reticulum (ER) stress signals and unconventional protein trafficking are frequently implicated in the expression of cell surface glycoproteins with high mannose glycans. However, TAP deficiency does not induce canonical ER stress, and factors relevant to unconventional secretory trafficking do not selectively affect HLA class I expression or their glycosylation in TAP-deficient cells. Rather, HLA class I cell surface expression in TAP-deficient cells is brefeldin A sensitive, similar to wild-type cells, implicating the conventional Golgi-dependent secretory route. Additionally, cell surface glycosylation changes in TAP-deficient cells are HLA class I-specific rather than global. Furthermore, other conditions that compromise HLA class I assembly, such as tapasin deficiency, also induce cell surface HLA class I with high mannose glycans. Overall, the excessive accumulation of misfolded HLA class I in the ER results in protein secretory trafficking combined with incomplete glycan processing, likely due to saturable glycan-dependent quality control mechanisms. Such imperfections in ER/Golgi quality control provide a novel mechanism to both preserve immunity and maintain ER homeostasis. Funding Sources This work was supported by the National Institutes of Health, grant NIH R01 AI044115 (to MR) and a WACCBIP-World Bank ACE Masters/PhD fellowship (WACCBIP+NCDs: Awandare). Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)