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. 2025 Jan 23;188(2):465-483.e22.
doi: 10.1016/j.cell.2024.10.046. Epub 2024 Nov 22.

snoRNA-facilitated protein secretion revealed by transcriptome-wide snoRNA target identification

Bei Liu  1 , Tong Wu  1 , Bernadette A Miao  2 , Fei Ji  3 , Shun Liu  1 , Pingluan Wang  1 , Yutao Zhao  1 , Yuhao Zhong  1 , Arunkumar Sundaram  4 , Tie-Bo Zeng  1 , Marta Majcherska-Agrawal  5 , Robert J Keenan  4 , Tao Pan  6 , Chuan He  7
Affiliations

snoRNA-facilitated protein secretion revealed by transcriptome-wide snoRNA target identification

Bei Liu et al. Cell. .

Abstract

Small nucleolar RNAs (snoRNAs) are non-coding RNAs known for guiding RNA modifications, including 2'-O-methylation (Nm) and pseudouridine (Ψ). While snoRNAs may also interact with other RNAs, such as mRNA, the full repertoire of RNAs targeted by snoRNA remains elusive due to the lack of effective technologies that identify snoRNA targets transcriptome wide. Here, we develop a chemical crosslinking-based approach that comprehensively detects cellular RNA targets of snoRNAs, yielding thousands of previously unrecognized snoRNA-mRNA interactions in human cells and mouse brain tissues. Many interactions occur outside of snoRNA-guided RNA modification sites, hinting at non-canonical functions beyond RNA modification. We find that one of these snoRNAs, SNORA73, targets mRNAs that encode secretory proteins and membrane proteins. SNORA73 also interacts with 7SL RNA, part of the signal recognition particle (SRP) required for protein secretion. The mRNA-SNORA73-7SL RNA interactions enhance the association of the SNORA73-target mRNAs with SRP, thereby facilitating the secretion of encoded proteins.

Keywords: RNA modifications Ψ and N(m); protein secretion; protein translocation; snoRNA molecular glue; snoRNA-7SL RNA interaction; snoRNA-mRNA interaction.

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Conflict of interest statement

Declaration of interests The University of Chicago has filed a patent application on the roles and engineering of snoRNA for protein secretion and membrane protein expression. C.H. is a scientific founder and member of the scientific advisory board and equity holder of Aferna Bio, Inc., and Ellis Bio Inc.; a scientific co-founder and equity holder of Accent Therapeutics, Inc.; and a member of the scientific advisory board of Element Biosciences and Rona Therapeutics. T.P. is a scientific cofounder of MesoRNA, LLC, and a scientific advisory board member of hc Biosciences, Inc.

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