ERp29, a general endoplasmic reticulum marker, is highly expressed throughout the brain

Abstract

ERp29 is a recently discovered resident of the endoplasmic reticulum (ER) that is abundant in brain and most other mammalian tissues. Investigations of nonneural secretory tissues have implicated ERp29 in a major role producing export proteins, but a molecular activity remains wanting for this functional orphan. Intriguingly, ERp29 appears to be heavily utilized in the cerebellum, a brain region not conventionally regarded as neurosecretory. To elucidate this functional quandary, we used immunochemical approaches to characterize the regional, cellular, and subcellular distributions of ERp29 in rat brain. Immunohistochemistry revealed ubiquitous expression in neuronal and nonneuronal cells, with a distinctive variation in somatic ERp29 levels. Highly expressing cells were found in diverse locations, implying that ERp29 is not biased towards the cerebellum functionally. Using immunolocalization data mined from the literature, a proteomic profile was developed to assess the functional significance of ERp29's characteristic expression pattern. Surprisingly, ERp29 correlated poorly with classical markers of neurosecretion, but strongly with a variety of major membrane proteins. Together with immunogold localization of ERp29 to somatic ER, these observations led to a novel hypothesis that ERp29 is involved primarily in production of endomembrane proteins rather than proteins destined for export. This study establishes ERp29 as a general ER marker for brain cells and provides a stimulating clue about ERp29's enigmatic function. ERp29 appears to have broad significance for neural pathophysiology, given its ubiquitous distribution and prominence in brain over classical ER residents like BiP and protein disulfide isomerase.

Identification and characterization of ERp29 in rat spermatozoa during epididymal transit

“…Mature ERp29 (25.6 kDa, MrZ29 000 on SDS-PAGE) has an N-terminal domain homologous to the thioredoxin-like domains in protein disulfide isomerase (PDI), and a C-terminal domain with similarities to the P5 subfamily of PDI , Liepinsh et al 2001, Sargsyan et al 2002a, 2002b, Mkrtchian & Sandalova 2006; a KDEL-variant motif at the C-terminus specifies retention in the ER. ERp29 is expressed ubiquitously in mammalian tissues, and homologous proteins have been identified in organisms as primitive as the fruit fly (Shnyder & Hubbard 2002, MacLeod et al 2004, Park et al 2005. These proteins are regarded to be specifically associated with the ER, mitochondria, Golgi, nuclei, or cell membrane (Huang et al 2002).…”

“…In humans, ERp29 is encoded by a single gene on chromosome 12 that has been highly conserved during mammalian evolution , Mkrtchian & Sandalova 2006. As ERp29 lacks the double cysteine motif, essential for PDI redox activity, it has been suggested that it plays a role in protein maturation and/or secretion, related to the chaperone function of PDI (Liepinsh et al 2001, Mkrtchian & Sandalova 2006, primarily in the production of endomembrane and secretory proteins (Shnyder & Hubbard 2002, MacLeod et al 2004. ERp29 is considered to be another major reticuloplasmin, thus adding distinct functionality to the ER machinery , MacLeod et al 2004, Hermann et al 2005.…”

“…As ERp29 lacks the double cysteine motif, essential for PDI redox activity, it has been suggested that it plays a role in protein maturation and/or secretion, related to the chaperone function of PDI (Liepinsh et al 2001, Mkrtchian & Sandalova 2006, primarily in the production of endomembrane and secretory proteins (Shnyder & Hubbard 2002, MacLeod et al 2004. ERp29 is considered to be another major reticuloplasmin, thus adding distinct functionality to the ER machinery , MacLeod et al 2004, Hermann et al 2005. All available data point to its important role in the formation of early secretory pathways within the ER (Mkrtchian et al 1998, Liepinsh et al 2001, Sargsyan et al 2002a, 2002b, Shnyder & Hubbard 2002, MacLeod et al 2004, Hermann et al 2005, Park et al 2005, Mkrtchian & Sandalova 2006, possibly by participating in the folding of proteins.…”

“…ERp29 is considered to be another major reticuloplasmin, thus adding distinct functionality to the ER machinery , MacLeod et al 2004, Hermann et al 2005. All available data point to its important role in the formation of early secretory pathways within the ER (Mkrtchian et al 1998, Liepinsh et al 2001, Sargsyan et al 2002a, 2002b, Shnyder & Hubbard 2002, MacLeod et al 2004, Hermann et al 2005, Park et al 2005, Mkrtchian & Sandalova 2006, possibly by participating in the folding of proteins. ERp29 assists in the protein folding as well as in the secretion of the secretory/plasma membrane proteins under the close cooperation with other ER chaperones and the ER stress signaler, PKR-like ER kinase (Park et al 2005).…”

“…ERp29 also has distinctive regulatory and biochemical properties, including a distinct lack of calcium-binding activity (Demmer et al 1997, Liepinsh et al 2001, Shnyder & Hubbard 2002, MacLeod et al 2004, Hermann et al 2005. Further evidence for ERp29's unique nature includes its novel tertiary structure (Liepinsh et al 2001), lack of classical ER stress-response elements (Sargsyan et al 2002a(Sargsyan et al , 2002b, ability to bind …”