Objective Superoxide dismutase (SOD) enzyme has implications in modulating the cell's redox state. The study aims to explore the host genetic factors that limit the heterologous expression of a thermostable SOD fromPotentilla atrosanguinea(Pa-SOD) inE.coli. Results It was observed that the heterologous expression of Pa-SOD inE.colidid not exhibit any enhancement after 1 h of induction. This led to the alteration in cell morphology and an increase in the doubling time ofE.colicells expressing Pa-SOD. Label-free quantification and MALDI-TOF/TOF-MS/MS analysis suggested differential expression of 81 proteins, of which 77 proteins were found to be downregulated and 4 were found to be upregulated in Pa-SOD expressing cells as compared to uninducedE.colicells. Functional analysis of downregulated proteins shows involvement in molecular function, biological process, and were the part of a cellular component. The STRING database revealed interaction of an essential autoregulatory protein, RNase E with other proteins involved in biosynthetic processes, protein biosynthesis and folding, and cell division. Further, validation of RNase E protein revealed upregulation ofrneat transcript level and downregulation of RNase E at protein level as compared to uninduced cells. Conclusions The observations suggested the operation of multifaceted mechanisms with a key role of RNase E that regulated the expression of Pa-SOD at the physiological and molecular level. Since Pa-SOD has commercial applications, identification and manipulation of these networked genetic factors could lead to improvement of host strain for large-scale production of biologically active Pa-SOD and other heterologous proteins.