9.B.23.  The TMEM106 (TMEM106) Family 

TMEM106B variants are genetically associated with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), and are considered a major risk factor for this disease. TMEM106B may also be involved in other pathologies such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Schwenk et al. 2014 combined loss-of-function experiments, live imaging and proteomics to unveil the physiological roles played by TMEM106B and its binding partner MAP6 in lysosomal function and transport. Neuronal TMEM106B plays a central role in regulating lysosomal size, motility and responsiveness to stress (Stagi et al. 2014). Single-nucleotide polymorphisms: rs5848 (GRN), rs1990622 (TMEM106B), and rs704180 (ABCC9) are associated with hippocampal sclerosis of aging (HS-Aging), a common high-morbidity neurodegenerative condition in elderly persons (Nelson et al. 2015). The up-regulation of TMEM106B may increase the risk of FTLD by directly causing neurotoxicity and a pathological phenotype linked to FTLD-TDP (Suzuki and Matsuoka 2016). Nicholson and Rademakers 2016 summarized what was known about TMEM106B and its role as a potential regulator of lysosomal function.

TMEM106C is overexpressed in hepatocellular carcinoma (HCC) cells, and inhibition of TMEM106C  suppressed the proliferation and metastasis of HCC (Duan et al. 2021). Upregulation of TMEM106C correlated with sex, tumor stage, tumor grade and prognosis. Overexpression of TMEM106C was linked to functional networks involving organelle fission and cell cycle signaling pathways through the regulation of CDK kinases, E2F1 transcription factors and miRNAs. Thus, TMEM106C contributes to malignant characteristics and poor prognosis in HCC (Duan et al. 2021).

TMEM106A is silenced by promoter region hypermethylation and suppresses gastric cancer growth by inducing apoptosis (Xu et al. 2014). It activates mouse peritoneal macrophages via the MAPK and NF-κB signaling pathways (Dai et al. 2015). It is a tumor suppressor in human renal cancer, and may play a role in prostate, breast and ovarian cancers (Wu et al. 2017; Babalyan et al. 2016; Du et al. 2018). It  inhibits cell proliferation and migration and induces apoptosis of lung cancer cells (Liu and Zhu 2018; Rizza et al. 2019). Moreover, inactivation of TMEM106A promotes lipopolysaccharide-induced inflammation via the MAPK and NF-kappaB signaling pathways in macrophages (Zhang et al. 2021).