Palmitoylation is the Switch that Assigns Calnexin to Quality Control or ER Calcium Signaling

Abstract

SummaryThe palmitoylation of calnexin serves to enrich calnexin on the mitochondria-associated membrane (MAM). Given a lack of information on the significance of this finding, we have investigated how this endoplasmic reticulum (ER)-internal sorting signal affects the functions of calnexin. Our results demonstrate that palmitoylated calnexin interacts with sarcoendoplasmic reticulum (SR) Ca 2+ transport ATPase (SERCA) 2b and that this interaction determines ER Ca 2+ content and the regulation of ER-mitochondria Ca 2+ crosstalk. In contrast, non-palmitoylated calnexin interacts with the oxidoreductase ERp57 and performs its well-known function in quality control. Interestingly, our results also show that calnexin palmitoylation is an ER-stress-dependent mechanism. Following a short-term ER stress, calnexin quickly becomes less palmitoylated, which shifts its function from the regulation of Ca 2+ signaling towards chaperoning and quality control of known substrates. These changes also correlate with a preferential distribution of calnexin to the MAM under resting conditions, or the rough ER and ER quality control compartment (ERQC) following ER stress. Our results have therefore identified the switch that assigns calnexin either to Ca 2+ signaling or to protein chaperoning.

The intrinsic and extrinsic effects of N-linked glycans on glycoproteostasis

“…Calnexin, which possesses a longer P-domain, can be expected to function through a similar mechanism. Interestingly, stress treatments decrease calnexin palmitoylation levels and support the reorganization of calnexin and calreticulin into the ERQC 77, 81 , a quality control compartment that is enriched for ERAD machinery such as ER mannosidase I, EDEM1, Derlin-1, and OS-9 81 . The lack of UGT1 and ERp57 in the ERQC suggests that the localization of calnexin into the ERQC might be a mechanism for ERAD substrate delivery to a dislocation and ubiquitination center, as calnexin substrate binding is expected to be weaker in the absence of ERp57 and UGT1.…”

“…Calnexin phosphorylation supports its increased association with ribosome-translocons, positioning the chaperone to aid in early glycoprotein maturation events 76 . Palmitoylation enriches calnexin localization to ribosome-translocons, as well as into the mitochondria-associated membranes (MAM) through its increased association with the sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) calcium pump 77 . The substrate binding activity of calnexin is regulated by calcium binding 78 .…”

ER-to-mitochondria miscommunication and metabolic diseases

“…One example of MAM plasticity is the redistribution and repurposing of the protein chaperone calnexin. In response to ER stress, calnexin moves from the ERmitochondria interface, where it regulates Ca 2+ homeostasis, to the ER protein folding compartment [42]. This exquisite mechanism not only contributes to restoring protein homeostasis via ER quality control, but also adjusts mitochondrial Ca 2+ uptake, in order to engage mitochondria in the adaptive response (see section 4 for further details).…”

The Lectin Chaperone Calnexin Is Involved in the Endoplasmic Reticulum Stress Response by Regulating Ca 2+ Homeostasis in Aspergillus nidulans

“…Palmitoylated calnexin interacts with sarcoplasmic/endoplasmic reticulum ATPase (SERCA2b), which determines ER [Ca 2ϩ ] and the regulation of ER-mitochondria Ca 2ϩ cross talk. In contrast, nonpalmitoylated calnexin interacts with the oxidoreductase ERp57 and performs its well-known function in ER quality control (45). However, SERCA pumps are absent in organisms such as fungi.…”