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A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.

ABSTRACT: We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation.

SUBMITTER: Oakes SR

PROVIDER: S-EPMC5695588 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.

Oakes Samantha R SR Gallego-Ortega David D Stanford Prudence M PM Junankar Simon S Au Wendy Wing Yee WWY Kikhtyak Zoya Z von Korff Anita A Sergio Claudio M CM Law Andrew M K AMK Castillo Lesley E LE Allerdice Stephanie L SL Young Adelaide I J AIJ Piggin Catherine C Whittle Belinda B Bertram Edward E Naylor Matthew J MJ Roden Daniel L DL Donovan Jesse J Korennykh Alexei A Goodnow Christopher C CC O'Bryan Moira K MK Ormandy Christopher J CJ

PLoS genetics 20171108 11

We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild ty ...[more]

PMID: 29117179

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Project description:BACKGROUND:Oligoadenylate synthetases (OASs) are widely distributed in Metazoa including sponges, fish, reptiles, birds and mammals and show large variation, with one to twelve members in any given species. Upon double-stranded RNA (dsRNA) binding, avian and mammalian OASs generate the second messenger 2'-5'-linked oligoadenylate (2-5A), which activates ribonuclease L (RNaseL) and blocks viral replication. However, how Metazoa shape their OAS repertoires to keep evolutionary balance to virus infection is largely unknown. We performed comprehensive phylogenetic and functional analyses of OAS genes from evolutionarily lower to higher Metazoa to demonstrate how the OAS repertoires have developed anti-viral activity and diversified their functions. RESULTS:Ancient Metazoa harbor OAS genes, but lack both upstream and downstream genes of the OAS-related pathways, indicating that ancient OASs are not interferon-induced genes involved in the innate immune system. Compared to OASs of ancient Metazoa (i.e. sponge), the corresponding ones of higher Metazoa present an increasing number of basic residues on the OAS/dsRNA interaction interface. Such an increase of basic residues might improve their binding affinity to dsRNA. Moreover, mutations of functional residues in the active pocket might lead to the fact that higher Metazoan OASs lose the ability to produce 3'-5'-linked oligoadenylate (3-5A) and turn into specific 2-5A synthetases. In addition, we found that multiple rounds of gene duplication and domain coupling events occurred in the OAS family and mutations at functionally critical sites were observed in most new OAS members. CONCLUSIONS:We propose a model for the expansion of OAS members and provide comprehensive evidence of subsequent neo-functionalization and sub-functionalization. Our observations lay the foundation for interrogating the evolutionary transition of ancient OAS genes to host defense genes and provide important information for exploring the unknown function of the OAS gene family.

Dataset Information

A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.

Publications

A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.

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