Lysosomal integrity is vital for cell homeostasis, but the underlying mechanisms are poorly understood. Here, we identify CLH-6, the C. elegans ortholog of the lysosomal Cl−/H+ antiporter ClC-7, as an important factor for protecting lysosomal integrity. Loss of CLH-6 affects lysosomal degradation, causing cargo accumulation and membrane rupture. Reducing cargo delivery or increasing CPL-1/cathepsin L or CPR-2/cathepsin B expression suppresses these lysosomal defects. Inactivation of CPL-1 or CPR-2, like CLH-6 inactivation, affects cargo digestion and causes lysosomal membrane rupture. Thus, loss of CLH-6 impairs cargo degradation, leading to membrane damage of lysosomes. In clh-6(lf) mutants, lysosomes are acidified as in wild type but contain lower chloride levels, and cathepsin B and L activities are significantly reduced. Cl− binds to CPL-1 and CPR-2 in vitro, and Cl− supplementation increases lysosomal cathepsin B and L activities. Altogether, these findings suggest that CLH-6 maintains the luminal chloride levels required for cathepsin activity, thus facilitating substrate digestion to protect lysosomal membrane integrity.

中文翻译：

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溶酶体氯转运蛋白 CLH-6 通过组织蛋白酶激活保护溶酶体膜完整性

溶酶体完整性对于细胞稳态至关重要，但其潜在机制尚不清楚。在这里，我们将 CLH-6（溶酶体 Cl−/H+ 逆向转运蛋白 ClC-7 的线虫直系同源物）确定为保护溶酶体完整性的重要因素。 CLH-6 的丢失会影响溶酶体降解，导致物质积累和膜破裂。减少货物输送或增加 CPL-1/组织蛋白酶 L 或 CPR-2/组织蛋白酶 B 表达可抑制这些溶酶体缺陷。 CPL-1 或 CPR-2 失活与 CLH-6 失活一样，会影响货物消化并导致溶酶体膜破裂。因此，CLH-6 的丢失会损害货物降解，导致溶酶体膜损伤。在 clh-6(lf) 突变体中，溶酶体与野生型一样被酸化，但氯含量较低，并且组织蛋白酶 B 和 L 活性显着降低。 Cl− 在体外与 CPL-1 和 CPR-2 结合，补充 Cl− 会增加溶酶体组织蛋白酶 B 和 L 的活性。总而言之，这些发现表明 CLH-6 维持组织蛋白酶活性所需的管腔氯化物水平，从而促进底物消化以保护溶酶体膜的完整性。