ER-to-Golgi transport machinery promotes the excessive cargo-triggered unfolded protein response in C. elegans.

ER-to-Golgi trafficking proteins ERGI-2 and ERGI-3 specifically activate the IRE-1-XBP-1 UPR pathway in response to excessive UNC-9 in C. elegans neurons.

• Why it matters: Understanding how secretory machinery components influence ER stress responses is crucial because disruptions can lead to diseases related to protein misfolding and trafficking defects, yet the specific roles of trafficking proteins in UPR activation remain unclear.
• What they did: Using genetics, imaging, and biochemical assays, the study examined neuronal overexpression of UNC-9 and the effects of ERGI-2 and ERGI-3 loss, revealing their cargo-specific role in coupling UNC-9 handling to UPR signaling.
• The result: Findings show ERGI-2 and ERGI-3 are essential for UPR activation triggered by UNC-9 overexpression, and their function reduces UNC-9 accumulation, highlighting their role as cargo-selective regulators linking secretory demand to ER stress responses.