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 in 2016, including 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). 

Since the initial identification of TMEM106B as a risk factor for frontotemporal lobar degeneration (FTLD), multiple genetic studies have found TMEM106B variants to modulate disease risk in a variety of brain disorders and healthy aging (Perneel and Rademakers 2022). Neurodegenerative disorders are typically characterized by inclusions of misfolded proteins, and since lysosomes are an important site for cellular debris clearance, lysosomal dysfunction has been linked to neurodegeneration. Consequently, many causal mutations or genetic risk variants implicated in neurodegenerative diseases encode proteins involved in endosomal-lysosomal function. As an integral lysosomal transmembrane protein, TMEM106B regulates several aspects of lysosomal function, and multiple studies have shown that proper TMEM106B protein levels are crucial for maintaining lysosomal health. Perneel and Rademakers 2022 reviewed TMEM106B research. When TMEM106B is compromised, protein and lipid clearance by the lysosome is delayed. As TMEM106B contains putative lipid- and LC3-binding sites, this may be its primary function (Shafit-Zagardo et al. 2023).

The structure and functions of NDR1/HIN1-like (NHL) proteins in plant development and response to environmental stresses have been reported (Amato et al. 2025). The NON-RACE-SPECIFIC DISEASE RESISTANCE 1/harpin-induced 1-LIKE (NHL) gene family plays pivotal roles, including pathogen resistance, abiotic stress tolerance, and developmental regulation, underscoring their functional versatility in developmental and physiological processes of plants. NHL proteins often localize to the plasma membrane and contain conserved motifs, including the LEA2 and transmembrane domains, enabling dynamic interactions with signalling molecules and transcription factors. The ability of NHL proteins to dimerize and oligomerize further enhances their regulatory potential in signalling pathways. The review by Amato et al. 2025 explores the structural and functional diversity of NHL proteins including their localizations, interacting proteins, and responses to abiotic and biotic stresses, ion transport, seed germination, and responses to phytohormones. Future research integrating phylogenetics, and advanced tools including artificial intelligence will unlock the full potential of this gene family for breeding climate-resilient crops and agricultural sustainability.

References: