Lysosomal exocytosis and resealing of damaged plasma membrane are essential for cellular homeostasis and tumor invasion. However, very little is known of the molecular machinery that regulates these physiological processes. Moreover, no mutations in any of the known regulators of lysosomal exocytosis in primary tumors of patients have been characterized. Here we demonstrate that RNF167-a, a lysosomal-associated ubiquitin ligase, negatively regulates lysosomal exocytosis by inducing perinuclear clustering of lysosomes. Importantly, we also characterized a set of novel natural mutations in RNF167-a, which are commonly found in diverse tumor types. We found that RNF167-a-K97N mutant, unlike the wild type, localizes in the cytoplasm and does not promote perinuclear lysosomal clustering. Furthermore, cells expressing RNF167-a-K97N exhibit dispersed lysosomes, increased exocytosis and enhanced plasma membrane repair. Interestingly, these functional features of RNF167-a-K97N were shared with a naturally occurring short version of RNF167 (isoform RNF167-b). In brief, the results presented here reveal a novel role of RNF167-a, as well as its natural variants RNF167-a-K97N and RNF167-b, as an upstream regulator of lysosomal exocytosis and plasma membrane resealing.

溶酶体胞吐作用和受损质膜的重新密封对于细胞稳态和肿瘤侵袭至关重要。然而，人们对调节这些生理过程的分子机制知之甚少。此外，尚未表征患者原发性肿瘤中任何已知的溶酶体胞吐作用调节因子的突变。在这里，我们证明 RNF167-a（一种溶酶体相关泛素连接酶）通过诱导溶酶体的核周聚集来负向调节溶酶体胞吐作用。重要的是，我们还表征了 RNF167-a 中的一组新的自然突变，这些突变常见于不同的肿瘤类型中。我们发现RNF167-a-K97N突变体与野生型不同，定位于细胞质中并且不促进核周溶酶体聚集。此外，表达 RNF167-a-K97N 的细胞表现出分散的溶酶体、增加的胞吐作用和增强的质膜修复。有趣的是，RNF167-a-K97N 的这些功能特征与天然存在的短版本 RNF167（亚型 RNF167-b）相同。简而言之，这里提出的结果揭示了 RNF167-a 及其天然变体 RNF167-a-K97N 和 RNF167-b 作为溶酶体胞吐作用和质膜重新密封的上游调节剂的新作用。