# TM9SF2 Maintains Golgi Integrity and Regulates Ricin-Induced Cytotoxicity

## TL;DR

This paper shows how TM9SF2 helps maintain Golgi structure and influences ricin's toxic effects by regulating cholesterol trafficking.

## Contribution

The novel role of TM9SF2 in ricin-induced cytotoxicity through cholesterol trafficking and Golgi integrity is revealed.

## Key findings

- TM9SF2 is essential for ricin-induced cytotoxicity within the nonaspanin family.
- Disruption of TM9SF2 causes cholesterol accumulation in the Golgi and fragmentation.
- Pharmacological manipulation of cholesterol metabolism restores Golgi integrity and ricin sensitivity.

## Abstract

TM9SF2 belongs to a family of highly conserved nonaspanin proteins, and has been frequently identified as one of the important host factors for a plethora of lethal pathogens and toxins in previous genome-wide screening studies. We reported herein a novel molecular mechanism of TM9SF2 in mediating the cytotoxicity of ricin, a type II ribosome-inactivating protein. We first showed that TM9SF2 displays a non-redundant requirement for ricin-induced cytotoxicity within the nonaspanin family. Then we found that genetic interference of TM9SF2 substantially affects/remodels intracellular cholesterol trafficking, which results in abnormal cholesterol accumulation in Golgi compartments and causes severe Golgi fragmentation. The disruption of Golgi integrity and network impedes the retrograde transport of ricin and thus attenuates ricin-induced cytotoxicity. We further verified this mechanism by pharmacological manipulation of cholesterol metabolism (e.g., by using A939572 and avasimibe, etc.), which well restores the integrity of the Golgi apparatus and reverses the ricin-resistant phenotype induced by TM9SF2 knockdown. Our finding provides new mechanistic insights into the pathology and toxicology of ricin and could potentially be applied to other ribosome-inactivating toxins.