Synthesis, Structure, and Function of Human Adenovirus Small Non-Coding RNAs

Abstract

Human adenoviruses (HAdVs) are common pathogens causing a variety of respiratory, ocular and gastrointestinal diseases. To accomplish their efficient replication, HAdVs take an advantage of viral small non-coding RNAs (sncRNAs), which have multiple roles during the virus lifecycle. Three of the best-characterized HAdV sncRNAs; VA RNA, mivaRNA and MLP-TSS-sRNA will be discussed in the present review. Even though VA RNA has been extensively characterized during the last 60 years, this multifunctional molecule continues to surprise us as more of its structural secrets unfold. Likely, the recent developments on mivaRNA and MLP-TSS-sRNA synthesis and function highlight the importance of these sncRNA in virus replication. Collectively, we will summarize the old and new knowledge about these three viral sncRNAs with focus on their synthesis, structure and functions.

Keywords: Dicer; MLP-TSS-sRNA; PKR; VA RNA; human adenovirus; miRISC; mivaRNA; sncRNA.

Figure 1

Structural overview of three Human adenovirus (HAdV) small non-coding RNAs (sncRNAs): virus-associated RNAI (VA RNAI), mivaRNAI and MLP-TSS-sRNA. The VA RNAI and mivaRNAI sequences are derived from HAdV-5 [22]. The MLP-TSS-sRNA sequence is from HAdV-37 [16]. Abbreviations: Cap; (m7G)-cap structure. Red line indicates the conserved tetranucleotide sequence (GGGU-ACCC), green line shows Dicer cleavage site within the terminal stem.

Figure 2

A simplified overview of the VA RNAI functions described in the text. Green arrow indicates the positive effect of VA RNAI to its interacting proteins (OAS1, RIG-I). Moreover, the positive effect of the proteins (Dicer, Exp5) on VA RNAI is shown by a green arrow. Black terminated line indicates the negative effect of VA RNAI on its associating proteins. VA RNAI has a dual effect on some of the proteins (OAS1, Dicer).

Figure 3

Proposed functions of the HAdV-5 mivaRNAs. (A) Validated targets (indicated in the yellow circles) of the mature 3’-mivaRNAI [19,21]. Since mutations in the 5’-mivaRNAI and 3’-mivaRNA sequences do not affect virus growth [86,89], the possibility that these mivaRNAs do not have an effect on virus growth is mentioned. (B) Proposed function of the 3’-mivaRNAII, which reduces CUL4 expression [94]. Low levels of the CUL4 protein will stabilize the c-Jun protein, which in turn enhances HAdV-5 growth. Red arrow, downregulation; green arrow, upregulation.

Figure 4

Proposed functional role of MLP-TSS-sRNA in HAdV-37 cells. The MLP-TSS-sRNA is in the complex with the Ago2 protein and anneals to its complementary sequence on two viral mRNAs (pTP and Pol). Abbreviations: C; (m7G)-cap structure, MLP; Major Late Promoter, E2; E2 promoter, pTP; preterminal protein, Pol; virus DNA polymerase, (A)n; poly(A) tail, Ago2; Argonaute 2 protein, MLP-TSS-sRNA; Major Late Promoter-Transcription Start Site-small RNA. Model is based on the study [16].