Lrrk1, leucine-rich repeat kinase 1, is a key protein kinase in humans. It belongs to the ROCO family of proteins, with a shared domain architecture with Lrrk2, but is linked to different diseases, specifically bone diseases [2]. Lrrk1 is involved in multiple cellular pathways including cilia disassembly, intracellular trafficking, and mitophagy [1,3,4]. Genetic models, such as knockout mice, are valuable tools to study its function.

In cultured cells, depletion of Lrrk1 impairs primary cilia resorption after serum stimulation, revealing its role in a novel PLK1-Lrrk1-NDEL1 pathway regulating cilia disassembly [1]. In mitophagy, Lrrk1 functions downstream of ULK1 and ULK2 in Parkin-mediated mitophagy, phosphorylating Rab7 at Ser-72 [4]. Lrrk1-deficient mice show severe osteopetrosis phenotypes due to osteoclast cytoskeletal dysfunction, as Lrrk1 regulates phosphorylation of L-plastin at Ser5 involved in actin assembly [5]. Lrrk1(-/-) mice also exhibit altered B1a-cell development, basal immunoglobulin production, and defects in IgG3 class-switch recombination, highlighting its role in B-cell responses and CARMA1-dependent NF-κB activation [6].

In summary, Lrrk1 plays essential roles in multiple biological processes. Studies using KO mouse models have revealed its significance in cilia disassembly, mitophagy, osteoclast function, and B-cell-related immune responses. These findings contribute to understanding diseases related to bone disorders and immune dysfunctions associated with Lrrk1.

References:

1. Hanafusa, Hiroshi, Kedashiro, Shin, Gotoh, Mako, Hisamoto, Naoki, Matsumoto, Kunihiro. 2022. LRRK1-mediated NDEL1 phosphorylation promotes cilia disassembly via dynein-2-driven retrograde intraflagellar transport. In Journal of cell science, 135, . doi:10.1242/jcs.259999. https://pubmed.ncbi.nlm.nih.gov/36254578/

2. Reimer, Janice M, Dickey, Andrea M, Lin, Yu Xuan, Reck-Peterson, Samara L, Leschziner, Andres E. 2023. Structure of LRRK1 and mechanisms of autoinhibition and activation. In Nature structural & molecular biology, 30, 1735-1745. doi:10.1038/s41594-023-01109-1. https://pubmed.ncbi.nlm.nih.gov/37857821/

3. Hanafusa, Hiroshi, Fujita, Keitaro, Kamio, Misa, Hisamoto, Naoki, Matsumoto, Kunihiro. 2023. LRRK1 functions as a scaffold for PTP1B-mediated EGFR sorting into ILVs at the ER-endosome contact site. In Journal of cell science, 136, . doi:10.1242/jcs.260566. https://pubmed.ncbi.nlm.nih.gov/36744428/

4. Fujita, Keitaro, Kedashiro, Shin, Yagi, Takuya, Matsumoto, Kunihiro, Hanafusa, Hiroshi. 2022. The ULK complex-LRRK1 axis regulates Parkin-mediated mitophagy via Rab7 Ser-72 phosphorylation. In Journal of cell science, 135, . doi:10.1242/jcs.260395. https://pubmed.ncbi.nlm.nih.gov/36408770/

5. Si, Mingjue, Goodluck, Helen, Zeng, Canjun, Mohan, Subburaman, Xing, Weirong. 2018. LRRK1 regulation of actin assembly in osteoclasts involves serine 5 phosphorylation of L-plastin. In Journal of cellular biochemistry, 119, 10351-10357. doi:10.1002/jcb.27377. https://pubmed.ncbi.nlm.nih.gov/30136304/

6. Morimoto, Keiko, Baba, Yoshihiro, Shinohara, Hisaaki, Toyofuku, Toshihiko, Kumanogoh, Atsushi. 2016. LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation. In Scientific reports, 6, 25738. doi:10.1038/srep25738. https://pubmed.ncbi.nlm.nih.gov/27166870/