The RNase a superfamily: Generation of diversity and innate host defense

Dyer, Kimberly D.; Rosenberg, Helene F.

doi:10.1007/s11030-006-9028-2

Cited by 132 publications

(131 citation statements)

References 146 publications

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…Some RNases are expressed in mucosal epithelia such as the intestinal tract, and in exocrine secretions such as saliva and milk. These observations, together with the reported antimicrobial and cytotoxic activities of some members of the family have led to the idea that the RNases function in host-defence (Dyer and Rosenberg, 2006;Boix and Nogues, 2007). One member of the RNase family, RNase5, has long been known to be present in milk (Maes et al, 1988).…”

Section: Pathogen-recognition Proteins In Cows' Milkmentioning

confidence: 99%

Host-defence-related proteins in cows’ milk

Wheeler

Smolenski

Harris

et al. 2012

Animal

View full text Add to dashboard Cite

Milk is a source of bioactive molecules with wide-ranging functions. Among these, the immune properties have been the best characterised. In recent years, it has become apparent that besides the immunoglobulins, milk also contains a range of minor immune-related proteins that collectively form a significant first line of defence against pathogens, acting both within the mammary gland itself as well as in the digestive tract of the suckling neonate. We have used proteomics technologies to characterise the repertoire of host-defence-related milk proteins in detail, revealing more than 100 distinct gene products in milk, of which at least 15 are known host-defence-related proteins. Those having intrinsic antimicrobial activity likely function as effector proteins of the local mucosal immune defence (e.g. defensins, cathelicidins and the calgranulins). Here, we focus on the activities and biological roles of the cathelicidins and mammary serum amyloid A. The function of the immune-related milk proteins that do not have intrinsic antimicrobial activity is also discussed, notably lipopolysaccharide-binding protein, RNase4, RNase5/angiogenin and cartilage-glycoprotein 39 kDa. Evidence is shown that at least some of these facilitate recognition of microbes, resulting in the activation of innate immune signalling pathways in cells associated with the mammary and/or gut mucosal surface. Finally, the contribution of the bacteria in milk to its functionality is discussed. These investigations are elucidating how an effective first line of defence is achieved in the bovine mammary gland and how milk contributes to optimal digestive function in the suckling calf. This study will contribute to a better understanding of the health benefits of milk, as well as to the development of high-value ingredients from milk.

show abstract

Section: Pathogen-recognition Proteins In Cows' Milkmentioning

confidence: 99%

Host-defence-related proteins in cows’ milk

Wheeler

Smolenski

Harris

et al. 2012

Animal

View full text Add to dashboard Cite

show abstract

“…RNase A ribonucleases have been implicated in a wide variety of physiologic functions and have been observed to promote angiogenesis, cellular apoptosis, and anti-tumor and anti-pathogen host defense via a complex array of seemingly unrelated molecular mechanisms (reviewed in Refs. [1][2][3][4][5][6][7][8].…”

mentioning

confidence: 99%

“…Given our ongoing interest in the role of RNase A ribonucleases in promoting host defense (5), in this work we explore the biologic activity and structure-function relationships of two closely related leukocyte-associated ribonucleases from the chicken, G. gallus. Chicken RNase A/angiogenin, named for structural similarity, as opposed to functional analysis, was identified by Nakano and Graf (20) from RNA from v-Myb transformed myeloblasts; ribonuclease superfamily-related (RSFR) 3 was cloned by Lobanenkov and co-workers (21) from chicken bone marrow as part of an unrelated subtractive hybridization study.…”

mentioning

confidence: 99%

Evolution and Function of Leukocyte RNase A Ribonucleases of the Avian Species, Gallus gallus

Nitto

Dyer

Czapiga

et al. 2006

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

In this study, we explore the evolution and function of two closely related RNase A ribonucleases from the chicken, Gallus gallus. Separated by ϳ10 kb on chromosome 6, the coding sequences of RNases A-1 and A-2 are diverging under positive selection pressure (d N > d S ) but remain similar to one another (81% amino acid identity) and to the mammalian angiogenins. Immunoreactive RNases A-1 and A-2 (both ϳ16 kDa) were detected in peripheral blood granulocytes and bone marrow. Recombinant proteins are ribonucleolytically active (k cat ‫؍‬ 2.6 and 0.056 s ؊1 , respectively), and surprisingly, both interact with human placental ribonuclease inhibitor. RNase A-2, the more cationic (pI 11.0), is both angiogenic and bactericidal; RNase A-1 (pI 10.2) has neither activity. We demonstrated via point mutation of the catalytic His 110 that ablation of ribonuclease activity has no impact on the bactericidal activity of RNase A-2. We determined that the divergent domains II (amino acids 71-76) and III (amino acids 89 -104) of RNase A-2 are both important for bactericidal activity. Furthermore, we demonstrated that these cationic domains can function as independent bactericidal peptides without the tertiary structure imposed by the RNase A backbone. These results suggest that ribonucleolytic activity may not be a crucial constraint limiting the ongoing evolution of this gene family and that the ribonuclease backbone may be merely serving as a scaffold to support the evolution of novel, nonribonucleolytic proteins.The RNase A ribonuclease gene family has been a tremendous source of information on unusual evolutionary constraints and their effects on protein structure and function at the molecular level. Although RNase A ribonucleases maintain invariant disulfide bonds and catalytic components that are necessary for RNA degradation, other regions have diverged dramatically. RNase A ribonucleases have been implicated in a wide variety of physiologic functions and have been observed to promote angiogenesis, cellular apoptosis, and anti-tumor and anti-pathogen host defense via a complex array of seemingly unrelated molecular mechanisms (reviewed in Refs. 1-8).The specific patterns of diversification are best understood among the RNase A ribonucleases of mammalian species. Four major RNase A lineages have been described in mammals (6) as follows: the pancreatic RNases, or RNases 1, which include the prototype, bovine pancreatic RNase A; a second group, including the eosinophil ribonucleases EDN (RNases 2), ECP (RNases 3), and RNases 6, 7, and 8; a third group that includes the RNases 4; and a final group that includes the angiogenins (RNases 5). There are also several genes, such as RNases 9 -13 in the human genome, that are distantly related to the RNase A family based on amino acid sequence homology but that are missing one or more elements necessary for enzymatic activity (9 -13). Interestingly, not all RNase A lineages are found in every mammalian species, and there are some recently described mammalian RNase A ribonucleases that...

show abstract

“…This protein class belongs to a super-family that includes an extensive network of distinct and divergent gene lineages [15]. Although all RNases of this super-family share invariant structural and 4 catalytic elements and some degree of enzymatic activity, the primary sequences have diverged significantly.…”

Section: And the March-inside (Markov Chain Invariantsmentioning

confidence: 99%