Unconventional protein secretion (UPS) pathways are conserved across species. However, the underlying mechanisms that regulate Golgi-bypassing UPS of integral proteins remain elusive. In this study, we show that RAB-8 and SMGL-1/NBAS are required for the UPS of integral proteins in C. elegans intestine. SMGL-1 resides in the ER-Golgi intermediate compartment and adjacent RAB-8-positive structures, and NRZ complex component CZW-1/ZW10 is required for this residency. Notably, SMGL-1 acts as a guanine nucleotide exchange factor for RAB-8, ensuring UPS of integral proteins by driving the activation of RAB-8. Furthermore, we show that Pseudomonas aeruginosa infection elevated the expression of SMGL-1 and RAB-8. Loss of SMGL-1 or RAB-8 compromised resistance to environmental colchicine, arsenite, and pathogenic bacteria. These results suggest that the SMGL-1/RAB-8-mediated UPS could integrate environmental signals to serve as a host defense response. Together, by establishing the C. elegans intestine as a multicellular model, our findings provide insights into RAB-8-dependent Golgi-bypassing UPS, especially in the context of epithelia in vivo.

中文翻译：

---

SMGL-1/NBAS 作为 RAB-8 GEF 调节非常规蛋白分泌

非常规蛋白质分泌（UPS）途径在物种间是保守的。然而，调节整合蛋白绕过高尔基体 UPS 的潜在机制仍然难以捉摸。在这项研究中，我们表明 RAB-8 和 SMGL-1/NBAS 是线虫肠道内整合蛋白 UPS 所必需的。 SMGL-1 存在于 ER-高尔基中间室和相邻的 RAB-8 阳性结构中，并且该驻留需要 NRZ 复合成分 CZW-1/ZW10。值得注意的是，SMGL-1 作为 RAB-8 的鸟嘌呤核苷酸交换因子，通过驱动 RAB-8 的激活来确保整合蛋白的 UPS。此外，我们发现铜绿假单胞菌感染升高了 SMGL-1 和 RAB-8 的表达。 SMGL-1 或 RAB-8 的缺失会损害对环境秋水仙碱、亚砷酸盐和致病菌的抵抗力。这些结果表明 SMGL-1/RAB-8 介导的 UPS 可以整合环境信号作为宿主防御反应。总之，通过将线虫肠道建立为多细胞模型，我们的研究结果提供了对 RAB-8 依赖性高尔基体绕过 UPS 的见解，特别是在体内上皮细胞的背景下。