IL-6 Evades KSHV-Mediated Hyperadenylation repression via CRM1-Dependent Nuclear Export

Area of Science:

• Virology
• Molecular Biology
• RNA Biology

Background:

• Kaposi's Sarcoma-associated Herpesvirus (KSHV) infection disrupts cellular homeostasis by degrading mRNA.
• Viral endonuclease SOX causes mRNA decay and nuclear RNA processing defects, including transcript hyperadenylation.
• Some mRNAs escape SOX-mediated decay and nuclear retention, indicating alternative export mechanisms.

Purpose of the Study:

• To investigate how KSHV infection affects mRNA poly(A) tail length and nuclear export dynamics.
• To identify the mechanisms by which specific host mRNAs evade KSHV-induced nuclear export blocks.
• To determine the role of the CRM1 pathway in the nuclear export of KSHV-affected transcripts.

Main Methods:

• Poly(A)-sequencing in KSHV-positive cells to analyze poly(A) tail length.
• G/I tailing and sPAT assays to study mRNA export dynamics.
• Inhibition of the CRM1 nuclear export pathway to assess its role in IL-6 export.

Main Results:

• KSHV infection globally increases mRNA poly(A) tail length.
• Hyperadenylated transcripts, including IL-6 mRNA, were identified in the cytoplasm, evading nuclear retention.
• IL-6 mRNA export is CRM1-dependent, not via the canonical NXF1-NXT1 pathway.
• CRM1 inhibition reduces IL-6 nuclear export and steady-state levels.

Conclusions:

• Select host mRNAs like IL-6 utilize the CRM1 pathway to bypass KSHV-imposed nuclear export blocks.
• Hyperadenylation does not solely dictate nuclear decay, as demonstrated by CRM1-mediated export of IL-6.
• CRM1 plays a crucial role in preserving cytoplasmic function of specific host transcripts during KSHV infection.
• This selective export mechanism offers insights into host-virus interactions and identifies CRM1 as a potential therapeutic target.