Targeted Mutation of Nuclear Bone Morphogenetic Protein 2 Impairs Secondary Immune Response in a Mouse Model.

Daniel S Olsen,Wesley A Goar,Paul R Reynolds,Eric Wilson,K Scott Weber,S Loyd Christensen,Brandt A Nichols,Kayla R Merriam,K Tyson Bailey,Laura C Bridgewater

doi:10.1155/2015/975789

Abstract

We recently identified a nuclear variant of the BMP2 growth factor, called nBMP2. In an effort to understand the function of this variant protein, we generated a mouse line in which BMP2 is expressed and functions normally, but nBMP2 is excluded from the nucleus. This novel mutation allows the study of nBMP2 without compromising BMP2 function. To determine whether nBMP2 plays a role in immune function, we performed a series of experiments in which we compared mouse survival, organ weights, immune cells numbers, and bacterial load in wild type and nBmp2NLStm mice following primary and secondary challenges with Staphylococcus aureus. Following primary challenge with S. aureus, wild type and nBmp2NLStm mice showed no differences in survival or bacterial load and generated similar numbers and types of leukocytes, although mutant spleens were smaller than wild type. Secondary bacterial challenge with S. aureus, however, produced differences in survival, with increased mortality seen in nBmp2NLStm mice. This increased mortality corresponded to higher levels of bacteremia in nBmp2NLStm mice and to a reduced enlargement of mutant spleens in response to the secondary infection. Together, these results suggest that the recently described nuclear variant of BMP2 is necessary for efficient secondary immune responses.

Highlights

Our group recently reported that a nuclear variant of the BMP2 growth factor is produced by alternative translation from a downstream start codon [1]
Kidneys, spleen, and lymph nodes from naıve wild type and nBmp2NLStm mutant mice were examined and weighed to determine whether differences were detectable before bacterial challenge
The spleens were an average of 26% smaller in mutant compared to wild type mice (p = 0.002) (Figure 1(a))

Summary

Introduction

Our group recently reported that a nuclear variant of the BMP2 growth factor is produced by alternative translation from a downstream start codon [1] This alternate translation results in a truncated protein that lacks the N-terminal signal peptide and is not recognized by the signal recognition particle (SRP) for delivery to the secretory pathway. In the absence of such cleavage, a bipartite nuclear localization signal that overlaps the proprotein convertase recognition sequence directs translocation of the variant protein to the nucleus [1]. Both nuclear and secreted BMP2 can be produced from the same mRNA transcript, and it is possible that some of the functions previously attributed to secreted BMP2 may be performed by nuclear BMP2 (nBMP2)

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Conclusion